NOVEL SULFONEUREA COMPOUNDS

Abstract

The present invention relates to compounds of formula (I): wherein A, B, L, X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in the specification. The present invention further relates to salts, solvates and prodrugs of such compounds, to pharmaceutical compositions comprising such compounds, and to the use of such compounds in the treatment and prevention of medical disorders and diseases, most especially by the inhibition of NLRP.sub.3.

##STR00001##

Claims

1. A compound of formula (I): ##STR00191## or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: A is a phenyl or 5- or 6-membered heteroaryl group, wherein A is substituted in the α position with B and in the α′ position with R.sup.4, and wherein A is optionally further substituted; B is a phenyl, 5- or 6-membered heteroaryl, or 4- to 6-membered saturated heterocyclic group, wherein B is substituted with -L-R.sup.2, and wherein B is optionally further substituted; X is O, NH or N(CN); Y is O or S; R.sup.1 is a C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, —NH(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl).sub.2, or —R.sup.20-R.sup.21 group, all optionally halo-substituted; L is a bond, —O—, —OC(R.sup.12).sub.2—, —OC(Ph)(R.sup.12)—, —OC(R.sup.12).sub.2C(R.sup.12).sub.2—, —C(R.sup.12).sub.2—, —C≡C— or —NR.sup.13—; R.sup.2 is a C.sub.3-C.sub.6 cycloalkyl, phenyl, 4- to 6-membered saturated heterocyclic, or 5- or 6-membered heteroaryl group, all optionally halo-substituted and/or optionally substituted with one, two or three substituents independently selected from cyano, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.4 cycloalkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 haloalkenyl, phenyl, benzyl, 4- to 6-membered saturated heterocyclyl, —CO(C.sub.1-C.sub.4 alkyl), —CO(C.sub.1-C.sub.4 haloalkyl), —CO.sub.2(C.sub.1-C.sub.4 alkyl), —CO.sub.2(C.sub.1-C.sub.4 haloalkyl), —CO.sub.2(benzyl), —OH, —O(C.sub.1-C.sub.4 alkyl), —O(C.sub.1-C.sub.4 haloalkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), —NH(C.sub.1-C.sub.4 haloalkyl), —N(C.sub.1-C.sub.4 alkyl).sub.2, —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 haloalkyl) and —N(C.sub.1-C.sub.4 haloalkyl).sub.2; either R.sup.4 is monovalent, and attached to A in the α′ position, and selected from C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl, C.sub.3-C.sub.6 cycloalkyl and phenyl, all optionally halo-substituted and/or optionally substituted with one or two substituents independently selected from oxo, —OH, —O(C.sub.1-C.sub.4 alkyl) and —O(C.sub.1-C.sub.4 haloalkyl); or R.sup.4 is divalent, and attached to A in the α′ and β′ positions, and selected from —CH.sub.2CH.sub.2CH.sub.2—, —CH═CHCH.sub.2—, —CH.sub.2CH═CH—, —CH.sub.2CH.sub.2O—, —OCH.sub.2CH.sub.2—, —CH.sub.2CH.sub.2CH.sub.2CH.sub.2— and —CH═CH—CH═CH—, all optionally halo-substituted and/or optionally substituted with one or two substituents independently selected from oxo, —OH, —O(C.sub.1-C.sub.4 alkyl) and —O(C.sub.1-C.sub.4 haloalkyl); each R.sup.12 is independently selected from hydrogen, halogen, methyl and halomethyl; R.sup.13 is hydrogen or methyl; R.sup.20 is a bond, C.sub.1-C.sub.4 alkylene or C.sub.1-C.sub.4 haloalkylene; R.sup.21 is a C.sub.3-C.sub.6 cycloalkyl, phenyl, 4- to 6-membered saturated heterocyclic, or 5- or 6-membered heteroaryl group, all optionally halo-substituted and/or optionally substituted with one or two substituents independently selected from cyano, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 haloalkenyl, —R.sup.22—OH, —R.sup.22—O(C.sub.1-C.sub.4 alkyl), —R.sup.22—O(C.sub.1-C.sub.4 haloalkyl), —R.sup.22—NH.sub.2, —R.sup.22—NH(C.sub.1-C.sub.4 alkyl), —R.sup.22—NH(C.sub.1-C.sub.4 haloalkyl), —R.sup.22—N(C.sub.1-C.sub.4 alkyl).sub.2, —R.sup.22—N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 haloalkyl), —R.sup.22—N(C.sub.1-C.sub.4 haloalkyl).sub.2 and —R.sup.22-R.sup.23; R.sup.22 is a bond, C.sub.1-C.sub.4 alkylene or C.sub.1-C.sub.4 haloalkylene; and R.sup.23 is a C.sub.3-C.sub.6 cycloalkyl or 4- to 6-membered saturated heterocyclic group, all optionally halo-substituted.

2. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein A is a phenyl group, substituted in the α position with B, substituted in the α′ position with R.sup.4, and optionally further substituted.

3. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein B is a pyridinyl group, substituted with -L-R.sup.2, and optionally further substituted.

4. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein Y is O.

5. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein: either R.sup.4 is monovalent, and attached to A in the α′ position, and selected from isopropyl, cyclopentyl, cyclohexyl and phenyl; or R.sup.4 is divalent, and attached to A in the α′ and β′ positions, and selected from —CH.sub.2CH.sub.2CH.sub.2—, —CH.sub.2CH.sub.2O— and —OCH.sub.2CH.sub.2—.

6. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein the compound is of formula (II): ##STR00192## wherein: X is O, NH or N(CN); R.sup.1 is a C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, —NH(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl).sub.2, or —R.sup.20-R.sup.21 group, all optionally halo-substituted; L is a bond, —O—, —OC(R.sup.12).sub.2— or —NR.sup.13—; R.sup.2 is a C.sub.3-C.sub.6 cycloalkyl or 4- to 6-membered saturated heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally halo-substituted and/or optionally substituted with one, two or three substituents independently selected from cyano, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.4 cycloalkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 haloalkenyl, phenyl, benzyl, —OH, —O(C.sub.1-C.sub.4 alkyl), —O(C.sub.1-C.sub.4 haloalkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), —NH(C.sub.1-C.sub.4 haloalkyl), —N(C.sub.1-C.sub.4 alkyl).sub.2, —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 haloalkyl) and —N(C.sub.1-C.sub.4 haloalkyl).sub.2; R.sup.3 is hydrogen or methyl; R.sup.4a is C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl or phenyl, all optionally halo-substituted; R.sup.5 is hydrogen; or R.sup.4a and R.sup.5 together form —CH.sub.2CH.sub.2CH.sub.2—, —CH═CHCH.sub.2—, —CH.sub.2CH═CH—, —CH.sub.2CH.sub.2O—, —OCH.sub.2CH.sub.2—, —CH.sub.2CH.sub.2CH.sub.2CH.sub.2— or —CH═CH—CH═CH—, all optionally halo-substituted; R.sup.6 is hydrogen, halogen or cyano; R.sup.7 is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 halocycloalkyl or halogen; each R.sup.12 is independently selected from hydrogen, halogen, methyl and halomethyl; R.sup.13 is hydrogen or methyl; R.sup.20 is a bond, C.sub.1-C.sub.4 alkylene or C.sub.1-C.sub.4 haloalkylene; R.sup.21 is a C.sub.3-C.sub.6 cycloalkyl, phenyl, 4- to 6-membered saturated heterocyclic, or 5- or 6-membered heteroaryl group, all optionally halo-substituted and/or optionally substituted with one or two substituents independently selected from cyano, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 haloalkenyl, —R.sup.22—OH, —R.sup.22—O(C.sub.1-C.sub.4 alkyl), —R.sup.22—O(C.sub.1-C.sub.4 haloalkyl), —R.sup.22—NH.sub.2, —R.sup.22—NH(C.sub.1-C.sub.4 alkyl), —R.sup.22—NH(C.sub.1-C.sub.4 haloalkyl), —R.sup.22—N(C.sub.1-C.sub.4 alkyl).sub.2, —R.sup.22—N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 haloalkyl), —R.sup.22—N(C.sub.1-C.sub.4 haloalkyl).sub.2 and —R.sup.22-R.sup.23; R.sup.22 is a bond, C.sub.1-C.sub.4 alkylene or C.sub.1-C.sub.4 haloalkylene; and R.sup.23 is a C.sub.3-C.sub.6 cycloalkyl or 4- to 6-membered saturated heterocyclic group, all optionally halo-substituted.

7. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 6, wherein: either R.sup.5 is hydrogen and R.sup.4a is isopropyl, cyclopentyl, cyclohexyl or phenyl; or R.sup.4a and R.sup.5 together form —CH.sub.2CH.sub.2CH.sub.2—, —CH.sub.2CH.sub.2O— or —OCH.sub.2CH.sub.2—.

8. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 6, wherein R.sup.6 is hydrogen or fluoro.

9. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 6, wherein R.sup.7 is hydrogen, methyl, cyclopropyl or fluoro.

10. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein X is O.

11. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.1 is C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, —NHMe, —NMe.sub.2, —NHEt, —NEt.sub.2 or —NMeEt, all optionally halo-substituted; or R.sup.1 is a C.sub.3-C.sub.6 cycloalkyl, phenyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, furanyl, thiophenyl, pyrazolyl or imidazolyl group, all optionally halo-substituted and/or optionally substituted with one or two substituents independently selected from C.sub.1-C.sub.3 alkyl, —R.sup.22—OH, —R.sup.22—O(C.sub.1-C.sub.3 alkyl), —R.sup.22—NH(C.sub.1-C.sub.3 alkyl), —R.sup.22—N(C.sub.1-C.sub.3 alkyl).sub.2 and —R.sup.22-R.sup.23; wherein R.sup.22 is a bond or C.sub.1-C.sub.4 alkylene; and R.sup.23 is a C.sub.3-C.sub.6 cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl or tetrahydropyranyl group.

12. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein L is a bond, —O— or —OCH.sub.2—.

13. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.2 is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl or tetrahydropyranyl group, all optionally substituted with one or two substituents independently selected from fluoro, C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3 alkenyl, phenyl, benzyl, —OH, —O(C.sub.1-C.sub.3 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.3 alkyl) and —N(C.sub.1-C.sub.3 alkyl).sub.2.

14. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, selected from the group consisting of: ##STR00193## ##STR00194## ##STR00195## ##STR00196## ##STR00197## ##STR00198## ##STR00199## ##STR00200##

15. (canceled)

16. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, and a pharmaceutically acceptable excipient.

17. A pharmaceutical composition as claimed in claim 16, wherein the pharmaceutical composition is an oral or topical pharmaceutical composition.

18. (canceled)

19. A method of treating or preventing a disease, disorder or condition in a subject, the method comprising the step of administering an effective amount of the compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1 to the subject, thereby treating or preventing the disease, disorder or condition, optionally wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

20. The method as claimed in claim 19, wherein the disease, disorder or condition is selected from: (i) inflammation; (ii) an auto-immune disease; (iii) cancer; (iv) an infection; (v) a central nervous system disease; (vi) a metabolic disease; (vii) a cardiovascular disease; (viii) a respiratory disease; (ix) a liver disease; (x) a renal disease; (xi) an ocular disease; (xii) a skin disease; (xiii) a lymphatic condition; (xiv) a psychological disorder; (xv) graft versus host disease; (xvi) allodynia; and (xvii) any disease where an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3.

21. The method as claimed in claim 19, wherein the disease, disorder or condition is selected from: (i) cryopyrin-associated periodic syndromes (CAPS); (ii) Muckle-Wells syndrome (MWS); (iii) familial cold autoinflammatory syndrome (FCAS); (iv) neonatal onset multisystem inflammatory disease (NOMID); (v) familial Mediterranean fever (FMF); (vi) pyogenic arthritis, pyoderma gangrenosum and acne syndrome (PAPA); (vii) hyperimmunoglobulinemia D and periodic fever syndrome (HIDS); (viii) Tumour Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome (TRAPS); (ix) systemic juvenile idiopathic arthritis; (x) adult-onset Still's disease (AOSD); (xi) relapsing polychondritis; (xii) Schnitzler's syndrome; (xiii) Sweet's syndrome; (xiv) Behcet's disease; (xv) anti-synthetase syndrome; (xvi) deficiency of interleukin 1 receptor antagonist (DIRA); and (xvii) haploinsufficiency of A20 (HA20).

22. (canceled)

23. The method as claimed in claim 19, wherein the compound is administered as a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

24. A method of inhibiting NLRP3 in a subject, comprising administering the compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1 to the subject thereby inhibiting NLRP3.

25. A method of analysing inhibition of NLRP3 or an effect of inhibition of NLRP3 by a compound, comprising contacting a cell or non-human animal with the compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, and analysing inhibition of NLRP3 or an effect of inhibition of NLRP3 in the cell or non-human animal by the compound.

Description

EXAMPLES—COMPOUND SYNTHESIS

[0247] All solvents, reagents and compounds were purchased and used without further purification unless stated otherwise.

Abbreviations

[0248] 2-MeTHF 2-methyltetrahydrofuran [0249] Ac.sub.2O acetic anhydride [0250] AcOH acetic acid [0251] aq aqueous [0252] B.sub.2Pin.sub.2 bis(pinacolato)diboron, also called 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) [0253] Boc tert-butyloxycarbonyl [0254] br broad [0255] Cbz carboxybenzyl [0256] CDI 1,1-carbonyl-diimidazole [0257] conc concentrated [0258] d doublet [0259] DABCO 1,4-diazabicyclo[2.2.2]octane [0260] DCE 1,2-dichloroethane, also called ethylene dichloride [0261] DCM dichloromethane [0262] DIPEA N,N-diisopropylethylamine, also called Hünig's base [0263] DMA dimethylacetamide [0264] DMAP 4-dimethylaminopyridine, also called N,N-dimethylpyridin-4-amine [0265] DME dimethoxyethane [0266] DMF N,N-dimethylformamide [0267] DMSO dimethyl sulfoxide [0268] EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide [0269] eq or equiv equivalent [0270] (ES.sup.+) electrospray ionization, positive mode [0271] Et ethyl [0272] EtOAc ethyl acetate [0273] EtOH ethanol [0274] h hour(s) [0275] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate [0276] HPLC high performance liquid chromatography [0277] LC liquid chromatography [0278] m multiplet [0279] m-CPBA 3-chloroperoxybenzoic acid [0280] Me methyl [0281] MeCN acetonitrile [0282] MeOH methanol [0283] (M+H).sup.+ protonated molecular ion [0284] MHz megahertz [0285] min minute(s) [0286] MS mass spectrometry [0287] Ms mesyl, also called methanesulfonyl [0288] MsCl mesyl chloride, also called methanesulfonyl chloride [0289] MTBE methyl tert-butyl ether, also called tert-butyl methyl ether [0290] m/z mass-to-charge ratio [0291] NaOtBu sodium tert-butoxide [0292] NBS 1-bromopyrrolidine-2,5-dione, also called N-bromosuccinimide [0293] NCS 1-chloropyrrolidine-2,5-dione, also called N-chlorosuccinimide [0294] NMP N-methylpyrrolidine [0295] NMR nuclear magnetic resonance (spectroscopy) [0296] Pd.sub.2(dba).sub.3 tris(dibenzylideneacetone) dipalladium(o) [0297] PdCl.sub.2 (dppf) [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), also called Pd(dppf)Cl.sub.2 [0298] PE petroleum ether [0299] Ph phenyl [0300] PMB p-methoxybenzyl, also called 4-methoxybenzyl [0301] prep HPLC preparative high performance liquid chromatography [0302] prep-TLC preparative thin layer chromatography [0303] PTSA p-toluenesulfonic acid [0304] q quartet [0305] RP reversed phase [0306] RT room temperature [0307] s singlet [0308] sat saturated [0309] SCX solid supported cation exchange (resin) [0310] sept septuplet [0311] t triplet [0312] T3P propylphosphonicanhydride [0313] TBME tert-butyl methyl ether, also called methyl tert-butyl ether [0314] TEA triethylamine [0315] TFA 2,2,2-trifluoroaceticacid [0316] THF tetrahydrofuran [0317] TLC thin layer chromatography [0318] wt % weight percent or percent by weight [0319] Xphos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

Experimental Methods

Nuclear Magnetic Resonance

[0320] NMR spectra were recorded at 300, 400 or 500 MHz. Spectra were measured at 298 K, unless indicated otherwise, and were referenced relative to the solvent resonance. The chemical shifts are reported in parts per million. Spectra were recorded using one of the following machines: [0321] a Bruker Avance III spectrometer at 400 MHz fitted with a BBO 5 mm liquid probe, [0322] a Bruker 400 MHz spectrometer using ICON-NMR, under TopSpin program control, [0323] a Bruker Avance III HD spectrometer at 500 MHz, equipped with a Bruker 5 mm SmartProbe™, [0324] an Agilent VNMRS 300 instrument fitted with a 7.05 Tesla magnet from Oxford instruments, indirect detection probe and direct drive console including PFG module, or [0325] an Agilent MercuryPlus 300 instrument fitted with a 7.05 Tesla magnet from Oxford instruments, 4 nuclei auto-switchable probe and Mercury plus console.

LC-MS

[0326] LC-MS Methods: Using SHIMADZU LCMS-2020, Agilent 1200 LC/G1956A MSD and Agilent 1200\G6110A, Agilent 1200 LC & Agilent 6110 MSD. Mobile Phase: A: 0.025% NH.sub.3.H.sub.2 in water (v/v); B: acetonitrile. Column: Kinetex EVO C18 2.1×30 mm, 5 μm.

Preparative Reversed Phase HPLC General Methods

[0327] Acidic prep HPLC (x-y % MeCN in water): Waters X-Select CSH column C18.5 μm (19×50 mm), flow rate 28 mL min-1 eluting with a H.sub.2O-MeCN gradient containing 0.1% v/v formic acid over 6.5 min using UV detection at 254 nm. Gradient information: 0.0-0.2 min, x % MeCN; 0.2-5.5 min, ramped from x % MeCN to y % MeCN; 5.5-5.6 min, ramped from y % MeCN to 95% MeCN; 5.6-6.5 min, held at 95% MeCN.

[0328] Acidic prep HPLC (x-y % MeOH in water): Waters X-Select CSH column C18.5 μm (19×50 mm), flow rate 28 mL min-1 eluting with a 10 mM aq formic acid-MeOH gradient over 7.5 min using UV detection at 254 nm. Gradient information: 0.0-1.5 min, x % MeOH; 1.5-6.8 min, ramped from x % MeOH to y % MeOH; 6.8-6.9 min, ramped from y % MeOH to 95% MeOH; 6.9-7.5 min. held at 95% MeOH.

[0329] Basic prep HPLC (x-y % MeCN in water): Waters X-Bridge Prep column C18.5 μm (19×50 mm), flow rate 28 mL min-1 eluting with a 10 mM NH.sub.4HCO.sub.3-MeCN gradient over 6.5 min using UV detection at 254 nm. Gradient information: 0.0-0.2 min, x % MeCN; 0.2-5.5 min, ramped from x % MeCN to y % MeCN; 5.5-5.6 min, ramped from y % MeCN to 95% MeCN; 5.6-6.5 min, held at 95% MeCN.

Synthesis of Intermediates

Intermediate L1: (4-(Dimethylamino)pyridin-1-ium-1-carbonyl)(methylsulfonyl)amide

[0330] ##STR00018##

[0331] A solution of methanesulfonamide (1.7 g, 17.87 mmol) and DMAP (4.37 g, 35.7 mmol) in MeCN (25 mL) was stirred at room temperature for 10 minutes. Diphenyl carbonate (4.21 g, 19.66 mmol) was then added and the reaction was stirred at room temperature for 5 days. The precipitate was filtered off, washed with MTBE and dried in vacuo to afford the title compound (1.67 g, 38%) as a white solid.

[0332] .sup.1H NMR (CDCl.sub.3) δ 9.07 (d, J=7.4 Hz, 2H), 6.74 (d, J=7.5 Hz, 2H), 3.35 (s, 6H), 3.20 (s, 3H).

[0333] The following intermediates were prepared according to the general procedure of Intermediate L1:

TABLE-US-00001 Int. Structure and name Characterisation and procedure L2 [00019] .sup.1H NMR (CDCl.sub.3) δ 9.08 (d, J = 7.4 Hz, 2H), 6.72 (d, J = 7.5 Hz, 2H), 3.34 (s, 6H), 3.03 (tt, J = 8.1, 4.9 Hz, 1H), 1.36-1.29 (m, 2H), 0.99-0.90 (m, 2H). From cyclopropanesulfonamide L3 [00020] From (N-methyl-N- aminosulfoamino)methane L4 [00021] From benzenesulfonamide L5 [00022] .sup.1H NMR (CDCl.sub.3) δ 8.24 (s, 2H), 6.55 (s, 2H), 3.06 (s, 6H), 1.48 (s, 9H). From 2-methyl-2-propanesulfonamide

Intermediate L6: N′-(tert-Butyldimethylsilyl)benzenesulfonimidamide

[0334] ##STR00023##

[0335] Triphenylphosphine (4.07 g, 15.51 mmol) and perchloroethane (3.67 g, 15.51 mmol) were dissolved in chloroform (45 mL) under N.sub.2 and stirred at 70° C. for 6 hours. Then the reaction was cooled to 0° C. and triethylamine (2.5 mL, 17.90 mmol) was added, followed by N-(tert-butyldimethylsilyl)benzenesulfonamide (3.25 g, 11.97 mmol) in chloroform (5 mL). The reaction mixture was stirred for 15 minutes. Then ammonia gas was bubbled through the reaction mixture for 15 minutes. The reaction mixture was stirred for 2 hours, and then filtered and the filtrate concentrated in vacuo. The resulting crude product was purified by flash chromatography (120 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (3.18 g, 49%) as a white powder.

[0336] .sup.1H NMR (DMSO-d6) δ 7.88-7.84 (m, 2H), 7.52-7.47 (m, 3H), 6.62 (br s, 2H), 0.87 (s, 9H), 0.01 (s, 3H), 0.01 (s, 3H).

[0337] LCMS m/z 271.2 (M+H).sup.+ (ES.sup.+).

Intermediate L7: Benzenesulfinamide

[0338] ##STR00024##

[0339] To a solution of methyl benzenesulfinate (500 mg, 3.20 mmol, 1 eq) in THF (1 mL) was added with LiHMDS (1M, 4.80 mL, 1.5 eq) at −78° C. The reaction mixture was stirred at −78° C. for 2 hours. Then a solution of NH.sub.4Cl (342 mg, 6.40 mmol, 2 eq) in H.sub.2O (5 mL) was added, and the resulting mixture was stirred at 25° C. for 1 hour. The reaction mixture was quenched with water (20 mL), and extracted with ethyl acetate (3×20 mL). The organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give the title compound (400 mg, 89%) as a white solid.

[0340] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.78-7.74 (m, 2H), 7.54-7.51 (m, 3H) and 4.36 (br s, 2H).

[0341] LCMS: m/z 141.9 (M+H).sup.+(ES.sup.+).

Intermediate L8: Methanesulfinamide

[0342] ##STR00025##

[0343] Ammonia gas (15 psi) was bubbled into THF (10 mL) at −78° C. for 10 minutes. Oxalyl chloride (39.18 mmol, 3.4 mL, 2 eq) was added into a solution of sodium methanesulfinate (2 g, 19.59 mmol, 1 eq) in THF (20 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 1 hour. Then the mixture was dropped into the above NH.sub.3/THF solution at 0° C. The resulting mixture was stirred at 20° C. for 12 hours. A solid formed. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to afford the title compound (0.9 g, crude) as a yellow solid.

[0344] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.30 (br s, 2H) and 2.66 (s, 3H).

Intermediate R.SUP.1.: 5-(2-Fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

[0345] ##STR00026##

[0346] A mixture of 5-bromo-2,3-dihydro-1H-inden-4-amine (10 g, 47.2 mmol), (2-fluoropyridin-4-yl)boronic acid (6.64 g, 47.2 mmol) and K.sub.2CO.sub.3 (19.6 g, 142 mmol) in dioxane (200 mL) and water (50 mL) was degassed with N.sub.2. PdC.sub.2 (dppf) (1.7 g, 2.323 mmol) was added and the reaction heated at 80° C. for 20 hours. After cooling to room temperature, the reaction mixture was partitioned between EtOAc (100 mL) and water (50 mL). The organic layer was dried (MgSO.sub.4) and evaporated in vacuo. The residue was purified by flash chromatography (0-50% EtOAc/isohexane) to afford the title compound (8.64 g, 79%) as a white solid.

[0347] .sup.1H NMR (DMSO-d6) δ 8.24 (d, J=5.2 Hz, 1H), 7.38 (ddd, J=5.2, 2.2, 1.4 Hz, 1H), 7.16 (d, J=1.4 Hz, 1H), 6.90 (d, J=7.6 Hz, 1H), 6.60 (d, J=7.6 Hz, 1H), 4.82 (s, 2H), 2.84 (t, J=7.5 Hz, 2H), 2.71 (t, J=7.4 Hz, 2H), 2.03 (p, J=7.5 Hz, 2H).

[0348] LCMS m/z 299.1 (M+H).sup.+ (ES.sup.+).

Intermediate R2: 2-Bromo-4-fluoro-6-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)aniline

[0349] ##STR00027##

[0350] A solution of 4-bromo-2-((1-methylpiperidin-4-yl)oxy)pyridine (5.98 g, 22.05 mmol), potassium acetate (8.66 g, 88 mmol), B.sub.2Pin.sub.2 (5.60 g, 22.05 mmol) and PdCl.sub.2 (dppf)-CH.sub.2C12 adduct (0.900 g, 1.103 mmol) in anhydrous 1,4-dioxane (100 mL) was evacuated and backfilled with nitrogen three times. The reaction mixture was stirred at 100° C. for 2 hours, and then cooled to room temperature. A solution of 2,6-dibromo-4-fluoroaniline (5.93 g, 22.05 mmol) in anhydrous 1,4-dioxane (20 mL) was added, followed by a solution of potassium carbonate (12.19 g, 88 mmol) in water (10 mL). Then the reaction mixture was stirred at 100° C. for 18 hours, diluted with EtOAc (250 mL), and washed with water (300 mL) and brine (300 mL). The organic phase was separated, dried (MgSO.sub.4) and filtered. Activated charcoal (10 g) was added to the filtrate. The slurry was stirred at 70° C. for 30 minutes, then filtered through a plug of Celite® whilst hot, directly loaded onto silica and concentrated under reduced pressure.

[0351] The crude product was purified by flash chromatography (0-10% (0.7 M ammonia/MeOH)/DCM) to afford the title compound (2.74 g, 31%) as a brown solid upon standing.

[0352] .sup.1HNMR(CDCl.sub.3) δ 8.21 (d, J=5.2 Hz, 1H), 7.24 (dd, J=7.7, 2.9 Hz, 1H), 6.91 (dd, J=5.2, 1.5 Hz, 1H), 6.84 (dd, J=8.6, 2.9 Hz, 1H), 6.78-6.77 (m, 1H), 5.17-5.09 (m, 1H), 4.08 (s, 2H), 2.80-2.70 (m, 2H), 2.43-2.31 (m, 5H), 2.15-2.07 (m, 2H), 1.94-1.83 (m, 2H).

[0353] LCMS m/z 380.1/382.1 (M+H).sup.+ (ES.sup.+).

Intermediate R.SUP.3.: 4-Bromo-3-methyl-2-((1-methylpiperidin-4-yl)oxy)pyridine

[0354] ##STR00028##

[0355] 1-Methylpiperidin-4-ol (0.67 g, 5.79 mmol) was added to a mixture of KO.sup.tBu (0.89 g, 7.89 mmol) in THF (5 mL) at room temperature. The reaction mixture was stirred for 1 hour, and then cooled in an ice bath. A solution of 4-bromo-2-fluoro-3-methylpyridine (1 g, 5.26 mmol) in THF (5 mL) was added. The mixture was warmed to room temperature, stirred for 2 days, and then partitioned between EtOAc (20 mL) and water (20 mL). The aqueous phase was extracted with EtOAc (20 mL). The organic phases were combined, dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified by flash chromatography (0-10% (0.7 M ammonia/MeOH)/DCM) to afford the title compound (1.30 g, 86%) as a colourless oil.

[0356] .sup.1H NMR (DMSO-d6) δ 7.85 (dd, J=5.4, 0.8 Hz, 1H), 7.19 (d, J=5.4 Hz, 1H), 5.02 (tt, J=8.1, 4.0 Hz, 1H), 2.59-2.52 (m, 2H), 2.26-2.20 (m, 5H), 2.17 (s, 3H), 1.97-1.86 (m, 2H), 1.74-1.62 (m, 2H).

[0357] LCMS m/z 285.1/287.1 (M+H).sup.+ (ES.sup.+).

Intermediate R4: 5-([2,2′-Bipyridin]-4-yl)-2,3-dihydro-1H-inden-4-amine

[0358] ##STR00029##

[0359] To a solution of 5-bromo-2,3-dihydro-1H-inden-4-amine (300 mg, 1.415 mmol) in dioxane (6 mL) was added B.sub.2Pin.sub.2 (395 mg, 1.556 mmol), potassium acetate (555 mg, 5.66 mmol), and PdC.sub.2 (dppf)-CH.sub.2Cl.sub.2 adduct (58 mg, 0.071 mmol). The reaction mixture was degassed (N.sub.2, 5 minutes) and evacuated and backfilled with N.sub.2 (×3) and stirred at 100° C. for 2 hours. Then the reaction mixture was cooled to ambient temperature, diluted with EtOAc (20 mL), and filtered through Celite® washing with EtOAc. The organics were concentrated in vacuo and to the residue was added 4-bromo-2,2′-bipyridine (0.111 mL, 0.707 mmol), Pd(PPh.sub.3).sub.4 (82 mg, 0.071 mmol), 2M aqueous solution of sodium carbonate (0.707 mL, 1.415 mmol), and toluene (9.5 mL).

[0360] Then the reaction mixture was heated to 100° C. for 16 hours, cooled to room temperature, diluted with EtOAc (30 mL), and washed with water (2×30 mL) and brine (30 mL). The organic extract was dried (phase separator) and concentrated in vacuo. The crude product was purified by flash chromatography (0-30% EtOAc/isohexane) to afford the title compound (52 mg, 23%) as a brown oil.

[0361] .sup.1H NMR (DMSO-d6) δ 8.74-8.67 (m, 2H), 8.48 (d, J=1.7 Hz, 1H), 8.45-8.41 (m, 1H), 7.97 (td, J=7.7, 1.8 Hz, 1H), 7.50 (dd, J=5.0, 1.8 Hz, 1H), 7.48-7.44 (m, 1H), 6.94 (d, J=7.6 Hz, 1H), 6.64 (d, J=7.6 Hz, 1H), 4.76 (br s, 2H), 2.86 (t, J=7.5 Hz, 2H), 2.74 (t, J=7.4 Hz, 2H), 2.10-2.01 (m, 2H).

[0362] LCMS m/z 288.1 (M+H).sup.+ (ES.sup.+).

[0363] The following intermediates were prepared according to the general procedure of Intermediate R.sup.4:

TABLE-US-00002 Int. Structure and name Characterisation and procedure R5 [00030] .sup.1H NMR (DMSO-d6) δ 8.68 (dd, J = 5.1, 0.8 Hz, 1H), 8.13-8.07 (m, 2H), 7.93-7.90 (m, 1H), 7.52-7.47 (m, 2H), 7.46-7.42 (m, 1H), 7.39 (dd, J = 5.0, 1.6 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 2.85 (t, J = 7.5 Hz, 2H), 2.73 (t, J = 7.3 Hz, 2H), 2.04 (p, J = 7.5 Hz, 2H). Two exchangeable protons not observed. LCMS m/z 287.2 (M + H).sup.+ (ES.sup.+). R6 [00031] .sup.1H NMR (DMSO-d6) δ 8.52 (d, J = 5.0 Hz, 1H), 7.36-7.16 (m, 2H), 6.87 (d, J = 7.6 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 4.67 (s, 2H), 4.01-3.89 (m, 2H), 3.52-3.39 (m, 2H), 3.01- 2.91 (m, 1H), 2.83 (t, J = 7.5 Hz, 2H), 2.71 (t, J = 7.3 Hz, 2H), 2.03 (p, J = 7.4 Hz, 2H), 1.88-1.76 (m, 4H). LCMS m/z 295.3 (M + H).sup.+ (ES.sup.+). R7 [00032] .sup.1H NMR (Methanol-d4) δ 8.63 (dd, J = 5.2, 0.8 Hz, 1H), 7.59-7.56 (m, 1H), 7.53 (dd, J = 5.3, 1.7 Hz, 1H), 7.43-7.40 (m, 1H), 7.38- 7.29 (m, 3H), 7.00 (d, J = 7.7 Hz, 1H), 6.74 (d, J = 7.7 Hz, 1H), 2.94 (t, J = 7.6 Hz, 2H), 2.82 (t, J = 7.4 Hz, 2H), 2.36 (s, 3H), 2.15 (p, J = 7.5 Hz, 2H). Two exchangeable protons not observed. LCMS m/z 301.1 (M + H).sup.+ (ES.sup.+). R8 [00033] .sup.1H NMR (DMSO-d6) δ 8.63-8.55 (m, 1H), 7.72-7.60 (m, 3H), 7.52-7.44 (m, 4H), 6.91 (d, J = 7.6 Hz, 1H), 6.62 (dd, J = 7.7, 2.6 Hz, 1H), 4.79 (s, 2H), 2.84 (t, J = 7.6 Hz, 2H), 2.72 (t, J = 7.4 Hz, 2H), 2.12-1.97 (m, 2H). LCMS m/z 311.2 (M + H).sup.+ (ES.sup.+).

Intermediate R9: 5-(2-((Tetrahydro-2H-pyran-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

[0364] ##STR00034##

[0365] Tetrahydro-2H-pyran-4-ol (98 mg, 0.964 mmol) in THF (1 mL) was added to a suspension of KO.sup.tBu (108 mg, 0.964 mmol) in dry THF (1 mL). The reaction mixture was stirred at room temperature for 1 hour, and then cooled to 0° C. 5-(2-Fluoropyridin-4-yl)-2,3-dihydro-H-inden-4-amine (Intermediate R1) (200 mg, 0.876 mmol) in THF (1 mL) was added. The reaction mixture was allowed to warm to room temperature, stirred for 16 hours, and then partitioned between EtOAc (20 mL) and water (10 mL). The organic layer was washed with water (10 mL), dried using a phase separator and concentrated in vacuo. The crude product was purified by flash chromatography (0-5% (0.7 M ammonia/MeOH)/DCM) to afford the title compound (131 mg, 46%) as a colourless solid.

[0366] .sup.1H NMR (DMSO-d6) δ 8.16 (d, J=5.3 Hz, 1H), 7.00 (dd, J=5.3, 1.5 Hz, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.75 (d, J=1.4 Hz, 1H), 6.58 (d, J=7.6 Hz, 1H), 5.25-5.18 (m, 1H), 4.66 (s, 2H), 3.91-3.83 (m, 2H), 3.54-3.47 (m, 2H), 2.83 (t, J=7.5 Hz, 2H), 2.70 (t, J=7.4 Hz, 2H), 2.04-1.99 (m, 4H), 1.72-1.60 (m, 2H).

[0367] LCMS m/z 311.2 (M+H).sup.+ (ES.sup.+).

[0368] The following intermediates were prepared according to the general procedure of Intermediate R.sup.9:

TABLE-US-00003 Int. Structure and name Characterisation and procedure R10 [00035] .sup.1H NMR (DMSO-d6) δ 8.16 (dd, J = 5.2, 0.7 Hz, 1H), 7.01 (dd, J = 5.3, 1.5 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.76-6.74 (m, 1H), 6.58 (d, J = 7.6 Hz, 1H), 5.08- 4.98 (m, 1H), 4.66 (s, 2H), 3.92-3.87 (m, 1H), 3.69-3.61 (m, 1H), 3.56-3.48 (m, 2H), 2.83 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.3 Hz, 2H), 2.11-2.00 (m, 3H), 1.85- 1.71 (m, 2H), 1.61-1.51 (m, 1H). LCMS m/z 311.0 (M + H).sup.+ (ES.sup.+). R11 [00036] .sup.1H NMR (DMSO-d6) δ 8.17 (d, J = 5.2 Hz, 1H), 7.43 (t, J = 7.3 Hz, 2H), 7.26- 7.14 (m, 4H), 6.99 (s, 1H), 6.89 (d, J = 7.6 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 4.76 (s, 2H), 2.83 (t, J = 7.5 Hz, 2H), 2.71 (t, J = 7.3 Hz, 2H), 2.02 (p, J = 7.4 Hz, 2H). LCMS m/z 303.2 (M + H).sup.+ (ES.sup.+). R12 [00037] .sup.1H NMR (DMSO-d6) δ 8.14 (dd, J = 5.2, 0.7 Hz, 1H), 7.00 (dd, J = 5.3, 1.5 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.74-6.70 (m, 1H), 6.57 (d, J = 7.6 Hz, 1H), 5.02 (p, J = 7.1 Hz, 1H), 4.71-4.61 (m, 4H), 4.55 (s, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.79-2.73 (m, 2H), 2.70 (t, J = 7.4 Hz, 2H), 2.30-2.23 (m, 2H), 2.05-2.00 (m, 2H). LCMS m/z 323.2 (M + H).sup.+ (ES.sup.+). R13 [00038] .sup.1H NMR (DMSO-d6) δ 8.61-8.53 (m, 2H), 8.16 (d, J = 5.3 Hz, 1H), 7.44 (s, 2H), 7.06 (dd, J = 5.3, 1.4 Hz, 1H), 6.94 (s, 1H), 6.88 (d, J = 7.6 Hz, 1H), 6.59 (d, J = 7.6 Hz, 1H), 5.46 (s, 2H), 4.71 (s, 2H), 2.83 (t, J = 7.5 Hz, 2H), 2.71 (t, J = 7.3 Hz, 2H), 2.03 (p, J = 7.5 Hz, 2H). LCMS m/z 318.52 (M + H).sup.+ (ES.sup.+). R14 [00039] .sup.1H NMR (DMSO-d6) δ 8.13 (d, J = 5.3 Hz, 1H), 6.99 (dd, J = 5.3, 1.5 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.74-6.73 (m, 1H), 6.57 4.65 (s, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.3 Hz, 2H), 2.63- 2.55 (m, 2H), 2.39-2.30 (m, 1H), 2.08- 1.99 (m, 8H), 1.89-1.80 (m, 2H). LCMS m/z 324.2 (M + H).sup.+ (ES.sup.+). R15 [00040] .sup.1H NMR (DMSO-d6) δ 8.16 (d, J = 5.2 Hz, 1H), 6.99 (dd, J = 5.3, 1.5 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.71 (d, J = 1.4 Hz, 1H), 6.58 (d, J = 7.6 Hz, 1H), 5.07 (tt, J = 8.4, 4.0 Hz, 1H), 4.65 (s, 2H), 2.94-2.88 (m, 1H), 2.83 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.3 Hz, 2H), 2.58-2.52 (m, 1H), 2.18 (s, 3H), 2.12-1.94 (m, 5H), 1.77-1.67 (m, 1H), 1.60-1.48 (m, 1H), 1.45-1.35 (m, 1H). LCMS m/z 324.2 (M + H).sup.+ (ES.sup.+). R16 [00041] .sup.1H NMR (CDCl.sub.3) δ 8.16 (d, J = 5.2 Hz, 1H), 7.02-6.92 (m, 2H), 6.82 (d, J = 1.4 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 5.11 (s, 1H), 3.74 (s, 2H), 2.95 (t, J = 7.5 Hz, 2H), 2.76 (t, J = 7.4 Hz, 4H), 2.46-2.26 (m, 5H), 2.22-2.04 (m, 4H), 1.95-1.78 (m, 2H). LCMS m/z 324.2 (M + H).sup.+ (ES.sup.+). R17 [00042] .sup.1H NMR (DMSO-d6) δ 8.16 (d, J = 5.3 Hz, 1H), 7.00 (dd, J = 5.3, 1.5 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.77 (d, J = 1.4 Hz, 1H), 6.58 (d, J = 7.6 Hz, 1H), 4.66 (s, 2H), 4.14 (d, J = 6.6 Hz, 2H), 3.92- 3.85 (m, 2H), 2.83 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.3 Hz, 2H), 2.09-1.98 (m, 3H), 1.71-1.64 (m, 2H), 1.39-1.27 (m, 2H). Two protons under water peak. LCMS m/z 325.2 (M + H).sup.+ (ES.sup.+). R18 [00043] .sup.1H NMR (DMSO-d6) δ 8.16 (d, J = 5.3 Hz, 1H), 6.99 (dd, J = 5.3, 1.5 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.74-6.73 (m, 1H), 6.57 (d, J = 7.6 Hz, 1H), 5.19-5.15 (m, 1H), 4.65 (s, 2H), 3.94-3.90 (m, 1H), 3.58-3.42 (m, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.69 (t, J = 7.3 Hz, 2H), 2.16-2.12 (m, 1H), 2.07-1.99 (m, 4H), 1.59-1.46 (m, 1H), 1.14 (d, J = 6.2 Hz, 3H). LCMS m/z 325.2 (M + H).sup.+ (ES.sup.+). R19 [00044] .sup.1H NMR (DMSO-d6) δ 8.19 (d, J = 5.3 Hz, 1H), 7.49 (d, J = 7.1 Hz, 2H), 7.39 (t, J = 7.2 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 7.04 (dd, J = 5.3, 1.5 Hz, 1H), 6.91- 6.81 (m, 2H), 6.58 (d, J = 7.6 Hz, 1H), 5.39 (s, 2H), 4.68 (s, 2H), 2.83 (t, J = 7.4 Hz, 2H), 2.71 (t, J = 7.4 Hz, 2H), 2.02 (p, J = 7.4 Hz, 2H). LCMS m/z 317.2 (M + H).sup.+ (ES.sup.+). R20 [00045] .sup.1H NMR (DMSO-d6) δ 8.15 (d, J = 5.2 Hz, 1H), 7.00 (dd, J = 5.3, 1.4 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.76 (s, 1H), 6.58 (d, J = 7.6 Hz, 1H), 4.65 (s, 2H), 4.13 (d, J = 6.1 Hz, 2H), 2.83 (t, J = 7.5 Hz, 2H), 2.80-2.74 (m, 1H), 2.70 (t, J = 7.4 Hz, 2H), 2.15 (s, 3H), 2.07-1.97 (m, 3H), 1.90-1.81 (m, 2H), 1.77-1.66 (m, 3H), 1.35-1.24 (m, 2H). R21 [00046] .sup.1H NMR (DMSO-d6) δ 8.15 (d, J = 5.2 Hz, 1H), 6.99 (dd, J = 5.3, 1.5 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.77-6.65 (m, 1H), 6.57 (d, J = 7.6 Hz, 1H), 5.44-5.25 (m, 1H), 4.64 (s, 2H), 3.78-3.72 (m, 1H), 3.71-3.63 (m, 1H), 2.82 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.3 Hz, 2H), 2.07-1.94 (m, 4H), 1.56-1.42 (m, 2H),), 1.23 (s, 3H), 1.21 (s, 3H). LCMS m/z 339.2 (M + H).sup.+ (ES.sup.+). R22 [00047] .sup.1H NMR (DMSO-d6) δ 8.20-8.07 (m, 1H), 6.97 (dt, J = 5.3, 1.1 Hz, 1H), 6.84 (dd, J = 7.6, 4.1 Hz, 1H), 6.70 (ddd, J = 6.1, 1.5, 0.7 Hz, 1H), 6.57 (dd, J = 7.6, 1.6 Hz, 1H), 5.10-4.97 (m, 1H), 4.64 (s, 2H), 3.54-3.37 (m, 1H), 3.19 (d, J = 4.3 Hz, 3H), 2.82 (t, J = 7.5 Hz, 2H), 2.69 (t, J = 7.4 Hz, 2H), 2.09-1.95 (m, 2H), 1.83- 1.58 (m, 4H), 1.51-1.40 (m, 4H). LCMS m/z 339.5 (M + H).sup.+ (ES.sup.+). R23 [00048] .sup.1H NMR (DMSO-d6) δ 8.19-8.12 (m, 1H), 7.34-7.14 (m, 5H), 7.00 (dd, J = 5.3, 1.5 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 1.6 Hz, 1H), 6.57 (d, J = 7.6 Hz, 1H), 4.65 (s, 2H), 4.49 (t, J = 7.0 Hz, 2H), 3.05 (t, J = 6.9 Hz, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.73-2.70 (m, 2H), 2.05-1.98 (m, 2H). LCMS m/z 331.2 (M + H).sup.+ (ES.sup.+). R24 [00049] .sup.1H NMR (DMSO-d6) δ 8.17 (d, J = 5.2 Hz, 1H), 7.02 (dd, J = 5.3, 1.5 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 6.78 (d, J = 1.4 Hz, 1H), 6.58 (d, J = 7.6 Hz, 1H), 5.28- 5.20 (m, 1H), 4.67 (s, 2H), 2.83 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.2 Hz, 2H), 2.15-1.95 (m, 8H), 1.92-1.82 (m, 2H). R25 [00050] .sup.1H NMR (DMSO-d6) δ 8.15 (dd, J = 5.2, 0.7 Hz, 1H), 6.98 (dd, J = 5.3, 1.5 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.76-6.66 (m, 1H), 6.57 (d, J = 7.6 Hz, 1H), 5.06- 4.96 (m, 1H), 4.64 (s, 2H), 2.93-2.77 (m, 4H), 2.69 (t, J = 7.4 Hz, 2H), 2.45- 2.35 (m, 2H), 2.09-1.89 (m, 4H), 1.69- 1.53 (m, 3H), 0.46-0.37 (m, 2H), 0.32- 0.28 (m, 2H). LCMS m/z 350.2 (M + H).sup.+ (ES.sup.+). R26 [00051] .sup.1H NMR (DMSO-d6) δ 8.17 (d, J = 5.2 Hz, 1H), 7.01 (dd, J = 5.3, 1.5 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.76 (s, 1H), 6.58 (d, J = 7.6 Hz, 1H), 5.28-5.20 (m, 1H), 4.66 (s, 2H), 3.97-3.88 (m, 1H), 3.75-3.66 (m, 1H), 3.38-3.33 (m, 1H), 3.25-3.17 (m, 1H), 2.83 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.4 Hz, 2H), 2.08-1.98 (m, 6H), 1.99-1.92 (m, 1H), 1.72-1.62 (m, 1H), 1.60-1.50 (m, 1H). LCMS m/z 352.2 (M + H).sup.+ (ES.sup.+). R27 [00052] .sup.1H NMR (DMSO-d6) δ 8.15 (d, J = 5.3 Hz, 1H), 6.97 (dd, J = 5.3, 1.5 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.69 (s, 1H), 6.57 (d, J = 7.7 Hz, 1H), 4.98-4.88 (m, 1H), 4.63 (s, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.3 Hz, 2H), 2.25-2.17 (m, 7H), 2.16-2.10 (m, 2H), 2.02 (p, J = 7.4 Hz, 2H), 1.89-1.82 (m, 2H), 1.48-1.30 (m, 4H). LCMS m/z 352.3 (M + H).sup.+ (ES.sup.+). R28 [00053] .sup.1H NMR (DMSO-d6) δ 8.14 (d, J = 5.3 Hz, 1H), 6.98 (dd, J = 5.3, 1.5 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.71 (d, J = 1.4 Hz, 1H), 6.57 (d, J = 7.6 Hz, 1H), 5.83 (ddt, J = 16.7, 10.3, 6.4 Hz, 1H), 5.21- 5.14 (m, 1H), 5.11 (dd, J = 10.2, 2.1 Hz, 1H), 5.01 (dt, J = 8.9, 4.6 Hz, 1H), 4.63 (d, J = 9.1 Hz, 2H), 2.98-2.89 (m, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.77- 2.66 (111, 2H), 2.23-2.14 (m, 2H), 2.05-1.94 (m, 4H), 1.71-1.61 (m, 2H). Two exchangeable protons not observed. LCMS m/z 350.3 (M + H).sup.+ (ES.sup.+). R29 [00054] .sup.1H NMR (DMSO-d6) δ 8.17 (d, J = 5.2 Hz, 1H), 7.24-7.18 (m, 2H), 7.00 (dd, J = 5.2, 1.5 Hz, 1H), 6.97 (d, J = 8.2 Hz, 2H), 6.85 (d, J = 7.6 Hz, 1H), 6.79-6.74 (m, 2H), 6.57 (d, J = 7.6 Hz, 1H), 5.23- 5.16 (m, 1H), 4.65 (s, 2H), 3.59-3.51 (m, 2H), 3.06-2.99 (m, 2H), 2.82 (t, J = 7.4 Hz, 2H), 2.70 (t, J = 7.2 Hz, 2H), 2.14-2.08 (m, 2H), 2.02 (p, J = 7.4 Hz, 2H), 1.83-1.73 (m, 2H). LCMS m/z 386.2 (M + H)+ (ES+). R30 [00055] .sup.1H NMR (DMSO-d6) δ 8.17 (d, J = 5.3 Hz, 1H), 8.15-8.06 (m, 1H), 7.52 (ddd, J = 8.9, 7.1, 2.0 Hz, 1H), 7.00 (dd, J = 5.3, 1.5 Hz, 1H), 6.90-6.81 (m, 2H), 6.75 (d, J = 1.4 Hz, 1H), 6.63-6.59 (m, 1H), 6.57 (d, J = 7.7 Hz, 1H), 5.27 (tt, J = 8.4, 4.0 Hz, 1H), 4.65 (s, 2H), 4.07-3.98 (m, 2H), 3.31-3.24 (m, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.69 (t, J = 7.4 Hz, 2H), 2.11-1.93 (m, 4H), 1.72-1.59 (m, 2H). LCMS m/z 387.3 (M + H).sup.+ (ES.sup.+). R31 [00056] .sup.1H NMR (DMSO-d6) δ 8.14 (d, J = 5.2 Hz, 1H), 7.35-7.29 (m, 4H), 7.27-7.21 (m, 1H), 6.98 (dd, J = 5.3, 1.5 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.73-6.71 (m, 1H), 6.57 (d, J = 7.6 Hz, 1H), 5.10-4.97 (m, 1H), 4.64 (s, 2H), 3.49 (s, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.76-2.64 (m, 4H), 2.28-2.18 (m, 2H), 2.07-1.94 (m, 4H), 1.75-1.62 (m, 2H). LCMS m/z 400.2 (M + H)+ (ES+). R32 [00057] .sup.1H NMR (DMSO-d6) δ 8.10 (d, J = 5.2 Hz, 1H), 7.53-7.46 (m, 4H), 7.34 (t, J = 7.7 Hz, 4H), 7.28-7.21 (m, 3H), 7.01 (dd, J = 5.3, 1.5 Hz, 1H), 6.97 (d, J = 1.4 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 6.58 (d, J = 7.7 Hz, 1H), 4.68 (s, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.3 Hz, 2H), 2.02 (p, J = 7.3 Hz, 2H). LCMS m/z 391.8 (M-H).sup.+ (ES.sup.+). R33 [00058] .sup.1H NMR (DMSO-d6) δ 8.37 (d, J = 5.3 Hz, 1H), 7.87 (d, J = 7.6, 2H), 7.64 (d, J = 7.5 Hz, 2H), 7.46 (t, J = 7.5 Hz, 2H), 7.31 (td, J = 7.5, 1.1 Hz, 2H), 7.26 (s, 1H), 7.17 (dd, J = 5.3, 1.5 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 687-6.85 (m, 1H), 6.58 (d, J = 76 Hz, 1H), 4.72 (s, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.4 Hz, 2H), 2.02 (p, J = 7.4 Hz, 2H). LCMS m/z 391.2 (M + H).sup.+ (ES.sup.+). R34 [00059] .sup.1H NMR (DMSO-d6) δ 8.16 (d, J = 5.3 Hz, 1H), 7.42-7.30 (m, 5H), 7.01 (dd, J = 5.3, 1.4 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.76 (s, 1H), 6.58 (d, J = 7.6 Hz, 1H), 5.27-5.19 (m, 1H), 5.10 (s, 2H), 4.65 (s, 2H), 3.84-3.73 (m, 2H), 2.83 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.4 Hz, 2H), 2.05-1.95 (m, 4H), 1.67- 1.56 (m, 2H). Two protons not observed. LCMS m/z 444.3 (M + H)+ (ES+). R35 [00060] .sup.1H NMR (DMSO-d6) δ 8.15 (d, J = 5.2 Hz, 1H), 6.96 (dd, J = 5.3, 1.5 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.70 (s, 1H), 6.58 (d, J = 7.6 Hz, 1H), 5.00-4.91 (m, 1H), 4.64 (s, 2H), 4.15 (s, 1H), 2.83 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.4 Hz, 2H), 2.02 (p, J = 7.4 Hz, 2H), 1.86-1.72 (m, 4H), 1.65-1.58 (m, 2H), 1.49-1.38 (m, 2H), 1.14 (s, 3H). LCMS m/z 339.3 (M + H)+ (ES+). R36 [00061] .sup.1H NMR (DMSO-d6) δ 8.15 (d, J = 5.2 Hz, 1H), 6.97 (dd, J = 5.3, 1.5 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 6.57 (d, J = 7.6 Hz, 1H), 5.17-5.09 (m, 1H), 4.65 (s, 2H), 4.19 (s, 1H), 2.83 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.4 Hz, 2H), 2.08-1.89 (m, 4H), 1.70-1.56 (m, 4H), 1.48-1.39 (m, 2H), 1.16 (s, 3H). LCMS m/z 339.3 (M + H).sup.+ (ES.sup.+). R37 [00062] .sup.1H NMR (DMSO-d6) δ 8.15 (dd, J = 5.3, 0.7 Hz, 1H), 6.99 (dd, J = 5.3, 1.5 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.73 (dd, J = 1.5, 0.7 Hz, 1H), 6.58 (d, J = 7.6 Hz, 1H), 5.41-5.33 (m, 1H), 4.65 (s, 2H), 4.10 (q, J = 5.3 Hz, 1H), 2.87-2.75 (m, 3H), 2.75-2.63 (m, 4H), 2.40-2.30 (m, 1H), 2.27 (s, 3H), 2.02 (p, J = 7.0 Hz, 2H), 1.88-1.80 (m, 1H). LCMS m/z 310.2 (M + H).sup.+ (ES.sup.+).

Intermediate R.SUP.38.: Phenyl (5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamate

[0369] ##STR00063##

[0370] 5-(2-((i-Methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate R.sup.6)(250 mg, 0.773 mmol) and phenyl carbonochloridate (97 μL, 0.773 mmol) were dissolved in DCM (5 mL), cooled to 0° C. and triethylamine (18 μL, 0.775 mmol) was added dropwise. The reaction was stirred at room temperature for 18 hours, then diluted with EtOAc (50 mL), washed with brine (2×30 mL), dried using a phase separator and concentrated in vacuo. The crude product was purified by flash chromatography (12 g cartridge, 0-10% (0.7 M ammonia/MeOH)/DCM) to afford the title compound (86 mg, 24%) as a tan solid.

[0371] .sup.1H NMR (DMSO-d6) δ 8.34 (d, J=5.3 Hz, 1H), 7.45-7.39 (m, 3H), 7.34-7.28 (m, 2H), 7.03 (dd, J=5.3, 1.5 Hz, 1H), 7.01-6.95 (m, 3H), 6.73 (s, 1H), 5.17-5.06 (m, 1H), 3.11-2.99 (m, 4H), 2.80-2.64 (m, 2H), 2.40-2.14 (m, 5H), 2.08-1.95 (m, 2H), 1.81-1.66 (m, 2H). 1H obscured by H.sub.2O peak.

[0372] LCMS m/z 444.4 (M+H).sup.+ (ES.sup.+).

Intermediate R.SUP.39.: 2-((1-Allylpiperidin-4-yl)oxy)-4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine

[0373] ##STR00064##

[0374] Triphosgene 0.14 g, 0.472 mmol) in THF (2 mL) was added dropwise to a cooled solution of 5-(2-((1-allylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate R.sup.28) (0.25 g, 0.715 mmol) and triethylamine (0.20 mL, 1.435 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 3 hours, filtered and the filtrate was concentrated in vacuo. The product was used without analysis in the next step.

[0375] The following intermediate was prepared according to the general procedure of Intermediate R.sup.39:

TABLE-US-00004 Int. Structure and name Characterisation and procedure R40 [00065] From Intermediate R60

Intermediate R41: 5-(2-(Morpholinomethyl)pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

Step A: (4-(4-Amino-2,3-dihydro-1H-inden-5-yl)pyridin-2-yl)methanol

[0376] ##STR00066##

[0377] To a solution of (4-bromopyridin-2-yl)methanol (200 mg, 1.064 mmol) in dioxane (6 mL) was added B.sub.2Pin.sub.2 (297 mg, 1.170 mmol), potassium acetate (418 mg, 4.25 mmol), and PdCl.sub.2 (dppf)-CH.sub.2Cl.sub.2 adduct (43 mg, 0.053 mmol). The reaction mixture was degassed (N.sub.2, 5 minutes) and evacuated and backfilled with N.sub.2 (×3). The reaction mixture was stirred at 100° C. for 2 hours, and then cooled to room temperature. A solution of 5-bromo-2,3-dihydro-1H-inden-4-amine (226 mg, 1.064 mmol) in dioxane (6 mL) was added, followed by a solution of potassium carbonate (588 mg, 4.25 mmol) in water (3 mL). The reaction mixture was stirred at 100° C. for 16 hours, and then cooled to room temperature, diluted with EtOAc (30 mL), and washed with water (2×30 mL) and brine (30 mL). The organic extract was dried (phase separator) and concentrated in vacuo. The crude product was purified by flash chromatography (0-10% (0.7 M ammonia/MeOH)/DCM) to afford the title compound (168 mg, 53%) as a sticky brown oil.

[0378] .sup.1H NMR (DMSO-d6) δ 8.49 (d, J=5.0 Hz, 1H), 7.51 (s, 1H), 7.27 (dd, J=5.1, 1.7 Hz, 1H), 6.87 (d, J=7.6 Hz, 1H), 6.61 (d, J=7.6 Hz, 1H), 5.38 (t, J=6.0 Hz, 1H), 4.67 (s, 2H), 4.60 (d, J=5.9 Hz, 2H), 2.84 (t, J=7.5 Hz, 2H), 2.72 (t, J=7.3 Hz, 2H), 2.04 (p, J=7.5 Hz, 2H).

[0379] LCMS m/z 241.1 (M+H).sup.+ (ES.sup.+).

Step B: 5-(2-(Morpholinomethyl)pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

[0380] ##STR00067##

[0381] To an ice cooled solution of (4-(4-amino-2,3-dihydro-H-inden-5-yl)pyridin-2-yl)methanol (169 mg, 0.701 mmol) and TEA (0.195 mL, 1.399 mmol) in DCM (10 mL) was added MsCl (0.065 mL, 0.839 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. Then the reaction mixture was diluted with DCM (10 mL), and washed with aqueous NaHCO.sub.3 (10 mL) and brine (10 mL). The organic extract was dried using a phase separator and concentrated under reduced pressure. The residue was dissolved in THF (6 mL) and halved. Morpholine (0.061 mL, 0.700 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by flash chromatography (0-10% (0.7 M ammonia/MeOH)/DCM) to afford the title compound (62.3 mg, 46%) as a dark orange oil.

[0382] .sup.1H NMR (DMSO-d6) δ 8.53-8.49 (m, 1H), 7.49-7.46 (m, 1H), 7.29 (dd, J=5.1, 1.7 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H), 6.61 (d, J=7.6 Hz, 1H), 4.67 (s, 2H), 3.62 (d, J=2.0 Hz, 2H), 3.59 (d, J=9.2 Hz, 4H), 2.84 (t, J=7.5 Hz, 2H), 2.71 (t, J=7.4 Hz, 2H), 2.45 (dd, J=8.5, 3.6 Hz, 4H), 2.08-1.99 (m, 2H).

[0383] LCMS m/z 310.2 (M+H).sup.+ (ES.sup.+).

Intermediate R42: 4-(4-Amino-2,3-dihydro-1H-inden-5-yl)-N-(1-methylpiperidin-4-yl)pyridin-2-amine

[0384] ##STR00068##

[0385] To a microwave vial was added 5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate R.sup.1) (500 mg, 2.190 mmol), 1-methylpiperidin-4-amine (2.74 mL, 21.90 mmol), DIPEA (0.765 mL, 4.38 mmol), and NMP (4 mL). The reaction was sealed and heated to 150° C. for 16 hours. The mixture was diluted with EtOAc (20 mL) and washed with water (2×20 mL). The organic extract was separated, dried using a phase separator and concentrated in vacuo. The crude product was purified by flash chromatography (0-10% (0.7 M ammonia/MeOH)/DCM) to afford the title compound (680 mg, 76%) as a pale orange solid.

[0386] .sup.1H NMR (DMSO-d6) δ 7.97 (d, J=5.1 Hz, 1H), 6.79 (d, J=7.6 Hz, 1H), 6.56 (d, J=7.5 Hz, 1H), 6.48-6.43 (m, 2H), 6.39 (d, J=7.5 Hz, 1H), 4.53 (s, 2H), 3.72-3.63 (m, 1H), 2.82 (t, J=7.5 Hz, 2H), 2.76-2.66 (m, 4H), 2.16 (s, 3H), 2.06-1.95 (m, 4H), 1.92-1.86 (m, 2H), 1.49-1.38 (m, 2H).

[0387] LCMS m/z 323.3 (M+H).sup.+ (ES.sup.+).

Intermediate R.SUP.43.: 4-Fluoro-2-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-6-(prop-1-yn-1-yl)aniline

[0388] ##STR00069##

[0389] Prop-1-yn-1-ylmagnesium bromide 0.5 M in THF (5.26 mL, 2.63 mmol) was added to zinc chloride 1.9 M in 2-MeTHF (1.39 mL, 2.64 mmol) dropwise at 0° C. and the resulting pale suspension was stirred at room temperature for 20 minutes. Then PdCl.sub.2 (dppf)-CH.sub.2Cl.sub.2 adduct (0.120 g, 0.147 mmol) and 2-bromo-4-fluoro-6-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)aniline (Intermediate R.sup.2) (0.4 g, 1.052 mmol) in anhydrous THF (2 mL) was added and the reaction stirred at 70° C. for 45 minutes. The reaction mixture was diluted with EtOAc (50 mL) and washed with water/brine (1:1, 60 mL). The organic phase was separated, dried (MgSO.sub.4), filtered and the crude directly loaded onto silica for purification. The crude product was purified by flash chromatography (0-10% (0.7 M ammonia/MeOH)/DCM) to afford the title compound (223 mg, 56%) as a purple solid.

[0390] .sup.1H NMR (CDCl.sub.3) δ 8.19 (d, J=5.2 Hz, 1H), 7.00 (dd, J=8.7, 3.0 Hz, 1H), 6.96-6.93 (m, 1H), 6.81-6.77 (m, 2H), 5.18-5.11 (m, 1H), 4.20 (br s, 2H), 2.81-2.74 (m, 2H), 2.46-2.35 (m, 5H), 2.18-2.10 (m, 5H), 1.97-1.86 (m, 2H).

[0391] LCMS m/z 340.2 (M+H).sup.+ (ES.sup.+).

[0392] The following intermediate was prepared according to the general procedure of Intermediate R.sup.43:

TABLE-US-00005 Int. Structure and name Characterisation and procedure R44 [00070] 1H NMR (CDCl.sub.3) δ 8.18 (d, J = 5.2 Hz, 1H), 6.95 (dd, J = 5.2, 1.5 Hz, 1H), 6.81- 6.76 (m, 2H), 6.71 (dd, J = 8.8, 3.0 Hz, 1H), 5.21 (br s, 1H), 3.59 (s, 2H), 2.91- 2.83 (m, 2H), 2.62 (br s, 2H), 2.46 (s, 3H), 2.39 (d, J = 7.2 Hz, 2H), 2.32-2.17 (m, 2H), 2.06-1.91 (m, 3H), 0.98 (d, J = 6.6 Hz, 6H). LCMS m/z 358.3 (M + H).sup.+ (ES.sup.+).

Intermediate R45: 4-Fluoro-2-isopropyl-6-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)aniline

[0393] ##STR00071##

[0394] Prepared according to the general procedure of 5-([2,2′-bipyridin]-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate R.sup.4) from 2-bromo-4-fluoro-6-isopropylaniline and 4-bromo-2-((1-methylpiperidin-4-yl)oxy)pyridine to afford the title compound (7.26 g, 78%) as a purple solid.

[0395] .sup.1H NMR (DMSO-d6) δ 8.19 (d, J=5.2 Hz, 1H), 7.00 (dd, J=5.3, 1.5 Hz, 1H), 6.92 (dd, J=10.2, 3.0 Hz, 1H), 6.76 (s, 1H), 6.73 (dd, J=9.0, 3.0 Hz, 1H), 5.01 (sept, J=8.5, 1H), 4.46 (s, 2H), 3.05 (sept, J=6.1 Hz, 1H), 2.71-2.61 (m, 2H), 2.22-2.13 (m, 5H), 2.04-1.93 (m, 2H), 1.75-1.63 (m, 2H), 1.17 (d, J=6.7 Hz, 6H).

[0396] LCMS m/z 344.2 (M+H).sup.+ (ES.sup.+).

[0397] The following intermediates were prepared according to the general procedure of Intermediate R.sup.45:

TABLE-US-00006 Int. Structure and name Characterisation and procedure R46 [00072] .sup.1H NMR (CDCl.sub.3) δ 8.17 (dd, J = 5.4, 0.7 Hz, 1H), 7.03 (dd, J = 5.3, 1.5 Hz, 1H), 6.96 (d, J = 7.7 Hz, 1H), 6.87 (t, J = 1.0 Hz, 1H), 6.76 (d, J = 7.7 Hz, 1H), 5.62 (ddt, J = 6.6, 4.5, 2.0 Hz, 1H), 4.07 (dd, J = 10.4, 4.6 Hz, 1H), 4.05-3.95 (m, 2H), 3.91 (td, J = 8.3, 4.4 Hz, 1H), 2.96 (t, J = 7.5 Hz, 2H), 2.76 (t, J = 7.4 Hz, 2H), 2.34-2.25 (m, 1H), 2.22-2.12 (m, 3H). Exchangeable NH.sub.2 signal not observed. LCMS 297.0 (M + H).sup.+ (ES.sup.+). R47 [00073] .sup.1H NMR (DMSO-d6) δ 8.14 (d, J = 5.3 Hz, 1H), 7.01-6.94 (m, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.73 (s, 1H), 6.58 (d, J = 7.6 Hz, 1H), 5.16 (p, J = 7.4 Hz, 1H), 4.65 (br s, 2H), 2.82 (t, J = 7.3 Hz, 2H), 2.70 (t, J = 7.2 Hz, 2H), 2.45-2.35 (m, 2H), 2.13-1.96 (m, 4H), 1.83-1.71 (m, 1H), 1.71-1.60 (m, 1H). LCMS m/z 281.0 (M + H).sup.+ (ES.sup.+). R48 [00074] .sup.1H NMR (DMSO-d6) δ 8.21 (d, J = 5.2 Hz, 1H), 7.05 (dd, J = 5.2, 1.4 Hz, 1H), 6.89-6.81 (m, 2H), 6.58 (d, J = 7.6 Hz, 1H), 4.69 (s, 2H), 4.21 (tt, J = 6.3, 3.1 Hz, 1H), 2.82 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.3 Hz, 2H), 2.06-1.99 (m, 2H), 0.81-0.67 (m, 4H). LCMS 267.0 (M + H).sup.+ (ES.sup.+). R49 [00075] .sup.1H NMR (DMSO-d6) δ 8.40 (d, J = 5.0 Hz, 1H), 7.31-7.28 (m, 1H), 7.15 (dd, J = 5.1, 1.7 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 6.59 (d, J = 7.6 Hz, 1H), 4.64 (br s, 2H), 2.83 (t, J = 7.5 Hz, 2H), 2.71 (t, J = 7.3 Hz, 2H), 2.12 (tt, J = 7.3, 5.5 Hz, 1H), 2.06-2.00 (m, 2H), 0.97-0.92 (m, 4H) LCMS 251.2 (M + H).sup.+ (ES.sup.+).

Intermediate R.SUP.50.: 2-Cyclopentyl-4-fluoro-6-(2-((i-methylpiperidin-4-yl)oxy)pyridin-4-yl) aniline

Step A: 2-(Cyclopent-1-en-1-yl)-4-fluoro-6-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)aniline

[0398] ##STR00076##

[0399] In an oven-dried round bottom flask, a mixture of PdCl.sub.2 (dppf)-CH.sub.2Cl.sub.2 adduct (0.064 g, 0.079 mmol), potassium carbonate (0.870 g, 6.30 mmol) and cyclopent-1-en-1-ylboronic acid (0.180 g, 1.609 mmol) was evacuated and backfilled with nitrogen twice. Then a solution of 2-bromo-4-fluoro-6-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)aniline (Intermediate R.sup.2) (0.6 g, 1.578 mmol) in anhydrous 1,4-dioxane (7 mL) and water (0.7 mL) was added. The resulting solution was evacuated and backfilled with nitrogen twice, before the reaction was stirred at 100° C. for 20 hours. The reaction mixture was diluted with EtOAc (100 mL), and washed with water (100 mL) and brine (100 mL). The organic phase was separated, dried (MgSO.sub.4), filtered and loaded directly onto silica for purification. The crude product was purified by flash chromatography (0-10% (0.7 M ammonia/MeOH)/DCM) to afford the title compound (319 mg, 28%) as a brown gum.

[0400] LCMS m/z 368.3 (M+H).sup.+ (ES.sup.+).

Step B: 2-Cyclopentyl-4-fluoro-6-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)aniline

[0401] ##STR00077##

[0402] 2-(Cyclopent-1-en-1-yl)-4-fluoro-6-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)aniline was dissolved in MeOH/EtOAc (1:1, 30 mL) and the solution passed through the H-Cube (1 mL/min, full H.sub.2, 40° C., 10% Pd/C catcart). The volatiles were removed under reduced pressure to afford the title compound (284 mg, 89%) as a pale yellow solid.

[0403] LCMS m/z 370.2 (M+H).sup.+ (ES.sup.+).

[0404] The following intermediate was prepared according to the general procedure of Intermediate R.sup.50:

TABLE-US-00007 Int. Structure and name Characterisation and procedure R51 [00078] LCMS m/z 384.5 (M + H).sup.+ (ES.sup.+). From Intermediate R2

Intermediate R52: 5-Fluoro-3-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-[1,1′-biphenyl]-2-amine

[0405] ##STR00079##

[0406] Prepared according to the general procedure of 2-(cyclopent-1-en-1-yl)-4-fluoro-6-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)aniline (Intermediate R.sup.50, step A) from 2-bromo-4-fluoro-6-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)aniline (Intermediate R.sup.2) and 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane to afford the title compound (300 mg, 33%) as a brown gum.

[0407] LCMS m/z 378.2 (M+H).sup.+ (ES.sup.+).

Intermediate R53: 5-(2-Cyclopropoxypyridin-4-yl)-2,3-dihydrobenzofuran-4-amine

Step A: 2-Cyclopropoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0408] ##STR00080##

[0409] A solution of 4-bromo-2-cyclopropoxypyridine (Intermediate R.sup.57, step A) (1 g, 4.67 mmol), B.sub.2Pin.sub.2 (1.305 g, 5-14 mmol), PdCl.sub.2 (dppf)-CH.sub.2Cl.sub.2 adduct (0.042 g, 0.051 mmol) and potassium acetate (1.375 g, 14.01 mmol) in anhydrous 1,4-dioxane (12 mL) was deoxygenated for 10 minutes, before the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite® rinsing with EtOAc (40 mL), and concentrated under reduced pressure to afford the title compound (1.52 g, 100%).

[0410] .sup.1H NMR (Chloroform-d) δ 8.24 (dd, J=4.9, 0.9 Hz, 1H), 7.22 (dd, J=4.9, 0.8 Hz, 1H), 7.16 (s, 1H), 4.34-4.06 (m, 1H), 1.33 (s, 12H), 0.87-0.77 (m, 2H), 0.77-0.72 (m, 2H).

Step B: 5-(2-Cyclopropoxypyridin-4-yl)-2,3-dihydrobenzofuran-4-amine

[0411] ##STR00081##

[0412] A mixture of 5-bromo-2,3-dihydrobenzofuran-4-amine (0.417 g, 1-950 mmol), 2-cyclopropoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.7 g, 2.145 mmol), K.sub.2CO.sub.3 (0.8 g, 29.0 mmol in 1.3 mL of water) in anhydrous 1,4-dioxane (6 mL) was deoxygenated for 10 minutes. PdC.sub.2 (dppf)-CH.sub.2Cl.sub.2 adduct (0.080 g, 0.097 mmol) was added and the solution was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered through a plug of Celite® rinsing with EtOAc (100 mL), directly loaded onto silica gel, and purified by flash chromatography (40 g cartridge, 0-100% EtOAc/isohexane) to afford impure product. The impure product was loaded onto a column of SCX (10 g) in DCM (5 mL). The column was washed with DCM (20 mL) and then the product was eluted with 0.7 M ammonia in MeOH (40 mL). The resultant mixture was concentrated in vacuo to afford the title compound (0.48 g, 74%) as a brown oil.

[0413] .sup.1H NMR (DMSO-d6) δ 8.17 (d, J=5.2 Hz, 1H), 7.02 (dd, J=5.3, 1.4 Hz, 1H), 6.89-6.76 (m, 2H), 6.13 (d, J=8.1 Hz, 1H), 4.92 (s, 2H), 4.53 (t, J=8.7 Hz, 2H), 4.20 (tt, J=6.4, 3.1 Hz, 1H), 3.00 (t, J=8.7 Hz, 2H), 0.89-0.72 (m, 2H), 0.71-0.67 (m, 2H).

[0414] LCMS m/z 269.0 (M+H).sup.+ (ES.sup.+).

[0415] The following intermediates were prepared according to the general procedure of Intermediate R.sup.53, step B:

TABLE-US-00008 Int. Structure and name Characterisation and procedure R54 [00082] .sup.1H NMR (DMSO-d6) δ 7.35-7.30 (m, 1H), 6.96-6.86 (m, 3H), 6.81 (d, J = 7.6 Hz, 1H), 6.56 (d, J = 7.5 Hz, 1H), 4.48-4.30 (m, 3H), 2.83 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.4 Hz, 2H), 2.66-2.56 (m, 2H), 2.26- 2.12 (m, 5H), 2.03 (p, J = 7.4 Hz, 2H), 1.98-1.88 (m, 2H), 1.74-1.57 (m, 2H). R55 [00083] .sup.1H NMR (DMSO-d6) δ 7.97 (d, J = 5.1 Hz, 1H), 6.69 (d, J = 5.1 Hz, 1H), 6.65 (d, J = 7.5 Hz, 1H), 6.54 (d, J = 7.5 Hz, 1H), 5.12-5.02 (m, 1H), 4.32 (s, 2H), 2.88-2.78 (m, 2H), 2.73-2.57 (m, 4H), 2.35-2.18 (m, 5H), 2.06-1.94 (m, 4H), 1.93 (s, 3H), 1.82-1.65 (m, 2H). LCMS m/z 338.2 (M + H).sup.+ (ES.sup.+). From Intermediate R3

Intermediate R56: 5-Bromo-6-methyl-2,3-dihydro-1H-inden-4-amine

Step A: N-(6-Bromo-4-nitro-2,3-dihydro-H-inden-5-yl)acetamide

[0416] ##STR00084##

[0417] Nitric acid (150 mL, 2350 mmol) was slowly added to sulfuric acid (150 mL) cooled to 0° C., while keeping the temperature below 20° C. The mixture was stirred for 10 minutes and added dropwise to a stirred mixture of N-(6-bromo-2,3-dihydro-H-inden-5-yl)acetamide (58 g, 228 mmol) in AcOH (300 mL) and sulfuric acid (150 mL), keeping the temperature below 30° C. The reaction mixture was stirred at room temperature for 4 hours and then poured onto ice/water (4.5 L total volume, 2.5 kg ice) and left to stand at room temperature for 18 hours. The solid was filtered, washed with water (2.5 L), and dried to afford the title compound (55 g, 80%) as an ochre powder.

[0418] .sup.1H NMR (DMSO-d6) δ 9.99 (s, 1H), 7.85 (s, 1H), 3.01-2.88 (m, 4H), 2.07 (p, J=7.5 Hz, 2H), 2.00 (s, 3H).

[0419] LCMS m/z 299.0/301.0 (M+H).sup.+ (ES.sup.+).

Step B: N-(6-Methyl-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide

[0420] ##STR00085##

[0421] A mixture of N-(6-bromo-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide (30 g, 100 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (14.02 mL, 100 mmol) and K.sub.2CO.sub.3 (34-7 g, 251 mmol) in dioxane (500 mL) and H.sub.2O (140 mL) was degassed with N.sub.2 for 15 minutes. PdCl.sub.2 (dppf)-CH.sub.2Cl.sub.2 adduct (4.10 g, 5.01 mmol) was added. The reaction mixture was heated at 100° C. for 16 hours, diluted with brine (300 mL), and extracted with EtOAc (2×800 mL). The organic layers were dried (MgSO.sub.4) and evaporated. The residue was triturated with EtOAc/isohexane (1:1 mixture, 400 mL) and the resultant solid was filtered, rinsing with hexanes, and dried in vacuo to afford the title compound (15.33 g, 56%) as a brown solid.

[0422] .sup.1H NMR (DMSO-d6) δ 9.65 (s, 1H), 7.41 (s, 1H), 2.98-2.87 (m, 4H), 2.20 (s, 3H), 2.07-2.03 (m, 2H), 1.99 (s, 3H).

[0423] LCMS m/z 235.2 (M+H).sup.+ (ES.sup.+).

Step C: 6-Methyl-4-nitro-2,3-dihydro-1H-inden-5-amine

[0424] ##STR00086##

[0425] N-(6-Methyl-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide (15.33 g, 65.4 mmol) was suspended in a mixture of EtOH (126 mL) and concentrated aq HCl (126 mL). The mixture was heated to reflux overnight and concentrated in vacuo. The residue was basified by portionwise addition of 2M aq NaOH (500 mL). The aqueous layer was extracted with DCM (5×200 mL), dried (MgSO.sub.4) and concentrated in vacuo to afford the title compound (15.18 g, 84%) as a brown solid.

[0426] .sup.1H NMR (DMSO-d6) δ 7.21 (s, 1H), 6.61 (s, 2H), 3.16 (t, J=7.5 Hz, 2H), 2.76 (t, J=7.6 Hz, 2H), 2.16 (s, 3H), 2.00-1.94 (m, 2H).

[0427] LCMS m/z 193.4 (M+H).sup.+ (ES.sup.+).

Step D: 5-Bromo-6-methyl-4-nitro-2,3-dihydro-1H-indene

[0428] ##STR00087##

[0429] A solution of 6-methyl-4-nitro-2,3-dihydro-1H-inden-5-amine (4.9 g, 20.39 mmol) and isopentyl nitrite (3 mL, 22.33 mmol) in MeCN (400 mL) was heated to 55° C., whereupon CuBr.sub.2 (4.56 g, 20.39 mmol) was added. The reaction mixture was heated to 70° C. and stirred for 1 hour. The reaction mixture was allowed to cool to room temperature and 1M HCl (200 mL) was added. The reaction mixture was extracted with DCM (3×200 mL). The organic phases were concentrated in vacuo and the crude product was purified by flash chromatography (0-20% EtOAc/isohexane) to afford the title compound (3.2 g, 60%) as a pale yellow solid.

[0430] .sup.1H NMR (DMSO-d6) δ 7.50 (s, 1H), 2.94-2.86 (m, 4H), 2.41 (s, 3H), 2.09 (p, J=7.6 Hz, 2H).

[0431] LCMS m/z 279.2 (M+Na).sup.+ (ES.sup.+).

Step E: 5-Bromo-6-methyl-2,3-dihydro-1H-inden-4-amine

[0432] ##STR00088##

[0433] A stirred mixture of 5-bromo-6-methyl-4-nitro-2,3-dihydro-1H-indene (8.42 g, 32.9 mmol), saturated aq NH.sub.4Cl (50 mL) and iron powder (7.34 g, 132 mmol) in EtOH/water (3:2, 80 mL) was stirred at 80° C. for 2 hours. After cooling to room temperature, the reaction was diluted with EtOAc (20 mL), and filtered through a pad of Celite®. The filtrate was diluted with water (10 mL). The layers were separated and the organic layer was dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by flash chromatography (0-50% EtOAc/isohexane) to afford the title compound (6.52 g, 75%) as a pink solid.

[0434] .sup.1H NMR (DMSO-d6) δ 6.48 (s, 1H), 4.94 (br s, 2H), 2.73 (t, J=7.5 Hz, 2H), 2.68 (t, J=7.4 Hz, 2H), 2.24 (s, 3H), 2.02-1.95 (m, 2H).

[0435] LCMS m/z 226/228 (M+H).sup.+ (ES.sup.+).

Intermediate R57: 5-(2-Cyclopropoxypyridin-4-yl)-6-methyl-2,3-dihydro-1H-inden-4-amine

Step A: 4-Bromo-2-cyclopropoxypyridine

[0436] ##STR00089##

[0437] To a mixture of cyclopropanol (1 g, 17.22 mmol) and 4-bromo-2-fluoropyridine (1.2 ml, 11.68 mmol) in NMP (13 mL) was added potassium tert-butoxide (1.9 g, 16.93 mmol) portionwise. The resultant mixture was stirred at room temperature for 30 minutes under nitrogen. Then the reaction mixture was diluted with EtOAc (so mL), washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and evaporated to afford the title compound (2.27 g, 83%) as a brown oil.

[0438] .sup.1H NMR (DMSO-d6) δ 8.12 (d, J=5.4 Hz, 1H), 7.28 (dd, J=5.4, 1.7 Hz, 1H), 7.16 (d, J=1.6 Hz, 1H), 4.21 (tt, J=6.2, 3.0 Hz, 1H), 0.80-0.74 (m, 2H), 0.70-0.66 (m, 2H). LCMS m/z 214/216 (M+H).sup.+ (ES.sup.+).

Step B: 5-(2-Cyclopropoxypyridin-4-yl)-6-methyl-2,3-dihydro-1H-inden-4-amine

[0439] ##STR00090##

[0440] To a solution of 4-bromo-2-cyclopropoxypyridine (189 mg, 0.885 mmol) in dioxane (5 mL) was added B.sub.2Pin.sub.2 (247 mg, 0.973 mmol), followed by potassium acetate (347 mg, 3.54 mmol) and PdC.sub.2 (dppf)-CH.sub.2Cl.sub.2 adduct (36 mg, 0.044 mmol). The reaction was degassed (N.sub.2, 5 minutes), evacuated and backfilled with N.sub.2 (×3) and stirred at 90° C. for 2 hours. Then the reaction mixture was cooled to room temperature. A solution of 5-bromo-6-methyl-2,3-dihydro-H-inden-4-amine (Intermediate R.sup.56) (200 mg, 0.885 mmol) in dioxane (3 mL) was added, followed by a solution of potassium carbonate (367 mg, 2.65 mmol) in water (1.5 mL). The reaction mixture was stirred at 90° C. for 16 hours, diluted with brine (10 mL), and extracted with DCM (2×20 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash chromatography (0-60% EtOAc/isohexane) to afford the title compound (135 mg, 52%) as a yellow oil.

[0441] .sup.1H NMR (DMSO-d6) δ 8.26 (d, J=5.1 Hz, 1H), 6.81 (dd, J=5.1, 1.3 Hz, 1H), 6.63 (d, J=1.2 Hz, 1H), 6.45 (s, 1H), 4.22 (tt, J=6.3, 3.1 Hz, 1H), 4.16 (s, 2H), 2.78 (t, J=7.5 Hz, 2H), 2.64 (t, J=7.3 Hz, 2H), 2.02-1.95 (m, 2H), 1.88 (s, 3H), 0.81-0.68 (m, 4H).

[0442] LCMS m/z 281.2 (M+H)+ (ES+).

[0443] The following intermediates were prepared according to the general procedure of Intermediate R.sup.57:

TABLE-US-00009 Int. Structure and name Characterisation and procedure R58 [00091] .sup.1H NMR (DMSO-d6) δ 8.22 (d, J = 5.2 Hz, 1H), 6.77 (dd, J = 5.2, 1.4 Hz, 1H), 6.56 (s, 1H), 6.45 (s, 1H), 5.57-5.52 (m, 1H), 4.16 (s, 2H), 3.96-3.92 (m, 1H), 3.89-3.80 (m, 2H), 3.80-3.74 (m, 1H), 2.78 (t, J = 7.5 Hz, 2H), 2.64 (t, J = 7.3 Hz, 2H), 2.30- 2.21 (m, 1H), 2.09-1.96 (m, 3H), 1.88 (s, 3H). LCMS m/z 311.2 (M + H).sup.+ (ES.sup.+). From Intermediate R56 R59 [00092] .sup.1H NMR (DMSO-d6) δ 8.21 (d, J = 5.2 Hz, 1H), 6.75 (dd, J = 5.2, 1.4 Hz, 1H), 6.54 (s, 1H), 6.45 (s, 1H), 5.27-5.15 (m, 1H), 4.14 (s, 2H), 3.93-3.80 (m, 4H), 2.78 (t, J = 7.5 Hz, 2H), 2.65 (t, J = 7.3 Hz, 2H), 2.11-1.93 (m, 4H), 1.88 (s, 3H), 1.72-1.56 (m, 2H). LCMS m/z 325.2 (M + H).sup.+ (ES.sup.+). From Intermediate R56 R60 [00093] .sup.1H NMR (DMSO-d6) δ 8.21 (d, J = 5.1 Hz, 1H), 6.73 (dd, J = 5.2, 1.4 Hz, 1H), 6.55- 6.47 (m, 1H), 6.45 (s, 1H), 5.01 (tt, J = 8.8, 4.2 Hz, 1H), 4.14 (s, 2H), 2.78 (t, J = 7.5 Hz, 2H), 2.74-2.58 (m, 4H), 2.27-2.09 (m, 5H), 2.06-1.93 (m, 4H), 1.88 (s, 3H), 1.76-1.63 (m, 2H). LCMS m/z 338.2 (M + H).sup.+ (ES.sup.+). From Intermediate R56 R61 [00094] .sup.1H NMR (DMSO-d6) δ 8.20 (d, J = 5.2 Hz, 1H), 6.72 (dd, J = 5.1, 1.4 Hz, 1H), 6.51 (s, 1H), 6.45 (s, 1H), 5.11-5.04 (m, 1H), 4.47 (d, J = 3.9 Hz, 1H), 4.14 (s, 2H), 3.67- 3.62 (m, 1H), 2.78 (t, J = 7.5 Hz, 2H), 2.68- 2.61 (m, 2H), 2.00 (q, J = 7.6 Hz, 2H), 1.94-1.85 (m, 5H), 1.73-1.66 (m, 2H), 1.64-1.58 (m, 4H). LCMS m/z 339.1 (M + H).sup.+ (ES.sup.+). From Intermediate R56 R62 [00095] .sup.1H NMR (DMSO-d6) δ 8.21 (d, J = 5.1 Hz, 1H), 6.75 (dd, J = 5.1, 1.4 Hz, 1H), 6.56 (s, 1H), 6.45 (s, 1H), 2.89-2.81 (m, 1H), 2.78 (t, J = 7.5 Hz, 2H), 2.70-2.60 (m, 2H), 2.18 (s, 3H), 2.08-1.95 (m, 4H), 1.96- 1.90 (m, 1H), 1.88 (s, 3H), 1.86-1.77 (m, 2H), 1.77-1.69 (m, 2H), 1.69-1.60 (m, 2H), 1.56-1.44 (m, 2H). LCMS m/z 352.6 (M + H).sup.+ (ES.sup.+). From Intermediate R56 R63 [00096] LCMS m/z 352.2 (M + H).sup.+ (ES.sup.+). From Intermediate R56 + Intermediate R3 R64 [00097] .sup.1H NMR (DMSO-d6) δ 8.19 (d, J = 5.1 Hz, 1H), 6.71 (dd, J = 5.1, 1.4 Hz, 1H), 6.48 (s, 1H), 6.44 (s, 1H), 4.98-4.87 (m, 1H), 4.12 (s, 2H), 2.78 (t, J = 7.6 Hz, 2H), 2.63 (t, J = 7.4 Hz, 2H), 2.25-2.05 (m, 9H), 1.98 (p, J = 7.5 Hz, 2H), 1.90-1.77 (m, 5H), 1.49- 1.26 (m, 4H). Only one isomer. LCMS m/z 366.6 (M + H).sup.+ (ES.sup.+). From Intermediate R56

Intermediate R65: 5-(2-(Cyclohexyloxy)pyridin-4-yl)-6-methyl-2,3-dihydro-1H-inden-4-amine

Step A: 5-(2-Fluoropyrdin-4-yl)-6-methyl-2,3-dihydro-H-inden-4-amine

[0444] ##STR00098##

[0445] A solution of 4-bromo-2-fluoropyridine (1.170 g, 6.65 mmol), KOAc (2.60 g, 26.5 mmol), B.sub.2Pin.sub.2 (1.685 g, 6.63 mmol) and PdCl.sub.2 (dppf)-CH.sub.2Cl.sub.2 adduct (0.271 g, 0.332 mmol) in 1,4-dioxane (20 mL) was heated at 100° C. for 2 hours under N.sub.2. Then the reaction mixture was cooled to room temperature and a solution 5-bromo-6-methyl-2,3-dihydro-1H-inden-4-amine (Intermediate R.sup.56) (1.5 g, 6.63 mmol) in 1,4-dioxane (5 mL) was added, followed by a solution of K.sub.2CO.sub.3 (3.67 g, 26.5 mmol) in water (2.5 mL). The reaction mixture was heated at 100° C. for 2 hours, diluted with EtOAc (75 mL), and washed with water (100 mL) and brine (100 mL). The organic phase was separated, dried (MgSO.sub.4) and evaporated in vacuo. The crude product was purified by flash chromatography (0-50% EtOAc/isohexane) to afford the title compound (940 mg, 55%) as a white solid.

[0446] .sup.1H NMR (CDCl.sub.3) δ 8.32 (d, J=5.0 Hz, 1H), 7.12 (dt, J=5.2, 1.6 Hz, 1H), 6.88 (s, 1H), 6.66 (s, 1H), 3.36 (s, 2H), 2.93 (t, J=7.5 Hz, 2H), 2.72 (t, J=7.4 Hz, 2H), 2.14 (p, J=7.5 Hz, 2H), 2.00 (s, 3H).

[0447] LCMS m/z 243.2 (M+H).sup.+ (ES.sup.+).

Step B: 5-(2-(Cyclohexyloxy)pyridin-4-yl)-6-methyl-2,3-dihydro-1H-inden-4-amine

[0448] ##STR00099##

[0449] KO.sup.tBu (0.132 g, 1.176 mmol) was added to cyclohexanol (0.163 mL, 1.568 mmol) in THF (3 mL). The reaction mixture was stirred at room temperature for 1 hour and then cooled to 0° C. 5-(2-Fluoropyridin-4-yl)-6-methyl-2,3-dihydro-1H-inden-4-amine (0.200 g, 0.784 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. Then the reaction mixture was partitioned between EtOAc (20 mL) and water (10 mL). The organic layer was washed with water (10 mL), dried (phase separator) and concentrated in vacuo. The crude product was purified by flash chromatography (0-25% EtOAc/isohexane) to afford the title compound (0.177 g, 61%) as a thick colourless oil.

[0450] .sup.1H NMR (DMSO-d6) δ 8.19 (d, J=5.1 Hz, 1H), 6.71 (dd, J=5.1, 1.4 Hz, 1H), 6.49 (s, 1H), 6.44 (s, 1H), 5.04-4.96 (m, 1H), 4.12 (s, 2H), 2.77 (t, J=7.5 Hz, 2H), 2.64 (t, J=7.3 Hz, 2H), 2.04-1.94 (m, 4H), 1.88 (s, 3H), 1.78-1.69 (m, 2H), 1.59-1.52 (m, 1H), 1.51-1.33 (m, 4H), 1.30-1.22 (m, 1H).

[0451] LCMS m/z 323.3 (M+H).sup.+ (ES.sup.+).

[0452] The following intermediate was prepared according to the general procedure of Intermediate R.sup.65:

TABLE-US-00010 Int. Structure and name Characterisation and procedure R66 [00100] .sup.1H NMR (DMSO-d6) δ 8.20 (t, J = 4.8 Hz, 1H), 6.73-6.71 (m, 1H), 6.51-6.50 (m, 1H), 6.45 (s, 1H), 5.12-5.06 (m, 0.5H), 5.05-4.98 (m, 0.5H), 4.13 (s, 2H), 3.25 (s, 1.5H), 3.24 (s, 1.5H), 2.78 (t, J = 7.5 Hz, 2H), 2.64 (t, J = 7.3 Hz, 2H), 2.13- 2.04 (m, 1H), 2.05-1.94 (m, 4H), 1.88 (d, J = 3.0 Hz, 3H) 1.84-1.69 (m, 3H), 1.69- 1.58 (m, 1H), 1.54-1.44 (m, 1H), 1.41- 1.30 (m, 1H). 50:50 mixture of cis/trans ring. LCMS m/z 353.3 (M + H).sup.+ (ES.sup.+). From Intermediate R56

Intermediate R.SUP.67

Phenyl (6-methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamate

Step A: 4-Bromo-2-((1-methylpiperidin-4-yl)oxy)pyridine

[0453] ##STR00101##

[0454] To a solution of KOtBu (41.13 g, 366.51 mmol, 1.5 eq) in THF (500 mL) was added 1-methylpiperidin-4-ol (33.77 g, 293.20 mmol, 1.2 eq) at 20° C. The reaction mixture was stirred for 1 hour. Then 4-bromo-2-fluoropyridine (43 g, 244.34 mmol, 1 eq) was added at 0° C. The reaction mixture was stirred at 20° C. for 12 hours, and then poured into water (500 mL). The aqueous phase was extracted with ethyl acetate (2×500 mL). The combined organic phases were washed with brine (2×500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, with 0.1% NH.sub.3.H.sub.2O, DCM:methanol 1:0 to 10:1) to give the title compound (61 g, 92%) as a yellow solid.

[0455] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.05 (d, 1H), 7.18 (dd, 1H), 7.06 (s, 1H), 4.98-4.93 (m, 1H), 2.62-2.59 (m, 2H), 2.16-2.11 (m, 5H) 1.94-1.91 (m, 2H) and 1.66-1.62 (m, 2H).

[0456] LCMS: m/z 273.0 (M+H).sup.+ (ES.sup.+).

Step B: 2-((1-Methylpiperidin-4-yl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0457] ##STR00102##

[0458] To a mixture of 4-bromo-2-((1-methylpiperidin-4-yl)oxy)pyridine (20 g, 73.76 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (24.35 g, 95.89 mmol, 1.3 eq) in dioxane (200 mL) was added PdCl.sub.2 (dppf) (3.24 g, 4.43 mmol, 0.06 eq) and KOAc (34.24 g, 348.88 mmol, 4.73 eq) in one portion under N.sub.2. Then the reaction mixture was heated to 100° C. for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by reserved phase flash chromatography (0.1% NH.sub.3.H.sub.2O-MeCN) to give the title compound (22.5 g, 96%) as a brown oil.

[0459] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.17-8.12 (m, 1H), 7.08-7.03 (m, 1H), 6.93-6.88 (m, 1H), 5.05-4.90 (m, 1H), 3.92-3.86 (m, 2H), 2.73-2.66 (m, 2H), 2.22 (s, 3H), 1.95-190 (m, 2H), 1.69-1.63 (m, 2H) and 1.06 (s, 12H).

[0460] LCMS: m/z 319.0 (M+H).sup.+ (ES.sup.+).

Step C: 6-Methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

[0461] ##STR00103##

[0462] To a mixture of 5-bromo-6-methyl-2,3-dihydro-1H-inden-4-amine (Intermediate R.sup.56) (40 g, 176.90 mmol, 1 eq) and 2-((1-methylpiperidin-4-yl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (78.81 g, 247.66 mmol, 1.4 eq) in dioxane (500 mL) and H.sub.2O (100 mL) was added K.sub.2CO.sub.3 (73.35 g, 530-71 mmol, 3 eq) and PdC.sub.2 (dppf) (7.77 g, 10.61 mmol, 0.06 eq) in one portion under N.sub.2. Then the reaction mixture was stirred at 100° C. for 12 hours. The reaction mixture was quenched with water (500 mL) and extracted with EtOAc (3×500 mL). The combined organic phases were washed with brine (500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was diluted with DCM (300 mL) and extracted with HCl (3×100 mL, 3 M). The combined aqueous phases were adjusted to pH 8 with saturated aqueous Na.sub.2CO.sub.3 solution, and then extracted with DCM (3×200 mL). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, PE:EtOAc 1:0 to 5:1, then DCM:MeOH 1:0 to 10:1 with 0.1% NH.sub.3.H.sub.2O) to give the title compound (50 g, 80% yield, 95.6% purity on HPLC) as a brown gum.

[0463] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.20 (d, 1H), 6.72 (dd, 1H), 6.50 (s, 1H), 6.44 (s, 1H), 5.02-4.97 (m, 1H), 4.13 (s, 2H), 2.77 (t, 2H), 2.67-2.61 (m, 4H), 2.17 (s, 3H), 2.16-2.11 (m, 2H), 2.02-1.94 (m, 4H), 1.87 (s, 3H) and 1.72-1.64 (m, 2H).

[0464] LCMS: m/z 338.2 (M+H).sup.+ (ES.sup.+).

Step D: Phenyl(6-methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamate

[0465] ##STR00104##

[0466] To a solution of 6-methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (1 g, 2.96 mmol, 1 eq) and phenyl carbonochloridate (463 mg, 2.96 mmol, 1 eq) in DCM (20 mL) was added TEA (300 mg, 2.96 mmol, 1 eq) at 0° C. Then the reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% TFA in water-MeCN) to give the title compound (350 mg, 20% yield, 95% purity on LCMS, TFA salt) as a yellow solid.

[0467] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.70-9.60 (m, 1H), 9.19 (s, 1H), 8.25 (t, 1H), 7.36-7.34 (m, 2H), 7.23-7.16 (m, 2H), 6.90-6.81 (m, 3H), 6.68-6.62 (m, 1H), 5.36-5.19 (m, 1H), 3.39-3.14 (m, 4H), 2.97-2.91 (m, 2H), 2.87-2.79 (m, 5H), 2.38-233 (m, 1H), 2.27-2.16 (m, 1H), 2.06 (d, 6H) and 1.90-1.78 (m, 1H).

[0468] LCMS: m/z 458.1 (M+H).sup.+ (ES.sup.+).

PREPARATION OF EXAMPLES

Example 1: N-((5-(2-(((1s,4s)-4-Methoxycyclohexyl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)methanesulfonamide

[0469] ##STR00105##

[0470] 5-(2-((4-Methoxycyclohexyl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate R.sup.22) (33 mg, 0.098 mmol) was added to a suspension of (4-(dimethylamino)pyridin-1-ium-1-carbonyl)(methylsulfonyl)amide (Intermediate L1) (0.1 mmol) in MeCN (1 mL) and the reaction mixture was stirred at 60° C. for 1 hour. The volatiles were evaporated, and the crude product dissolved in DMSO (1 mL), filtered, and purified by basic prep HPLC (20-50% MeCN in water) to afford the title compound (3 mg, 7%) as a white solid.

[0471] .sup.1H NMR (DMSO-d6) δ 8.11 (d, J=5.3 Hz, 1H), 7.57 (s, 1H), 7.17 (d, J=7.7 Hz, 1H), 7.10 (d, J=7.7 Hz, 1H), 6.92 (dd, J=5.3, 1.5 Hz, 1H), 6.72 (s, 1H), 5.10-5.02 (m, 1H), 3.24 (s, 3H), 2.93 (t, J=7.4 Hz, 2H), 2.87 (s, 3H), 2.82 (t, J=7.4 Hz, 2H), 2.02 (p, J=7.5 Hz, 2H), 1.83-1.68 (m, 6H), 1.68-1.60 (m, 2H). One exchangeable proton not observed, on proton under DMSO.

[0472] LCMS m/z 460.3 (M+H).sup.+ (ES.sup.+).

[0473] The following examples were prepared according to the general procedure of Example 1:

TABLE-US-00011 Ex. Structure and name Characterisation and procedure  2 [00106] .sup.1H NMR (DMSO-d6) δ 8.10 (d, J = 5.2 Hz, 1H), 7.12 (d, J = 7.7 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.93 (dd, J = 5.3, 1.5 Hz, 1H), 6.72 (s, 1H), 5.04-4.94 (m, 1H), 3.29- 3.18 (m, 4H), 2.91 (t, J = 7.5 Hz, 2H), 2.83 (t, J = 7.4 Hz, 2H), 2.75 (s, 3H), 2.10- 1.88 (m, 6H), 1.53-1.42 (m, 2H), 1.41- 1.30 (m, 2H). One exchangeable proton not observed. One proton under DMSO. LCMS m/z 460.3 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R22  3 [00107] .sup.1H NMR (DMSO-d6) δ 8.15 (d, J = 5.3 Hz, 1H), 7.89 (br s, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.89 (dd, J = 5.2, 1.5 Hz, 1H), 6.69 (s, 1H), 5.15-5.07 (m, 1H), 4.18 (s, 1H), 3.03 (s, 3H), 2.94 (t, J = 7.4 Hz, 2H), 2.81 (t, J = 7.4 Hz, 2H), 2.03 (p, J = 7.4 Hz, 2H), 1.99-1.89 (m, 2H), 1.71-1.55 (m, 4H), 1.50-1.38 (m, 2H), 1.15 (s, 3H). One exchangeable proton not observed. LCMS m/z 460.4 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R36  4 [00108] .sup.1H NMR (DMSO-d6) δ 8.14 (d, J = 5.3 Hz, 1H), 7.87 (br s, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.90 (dd, J = 5.3, 1.4 Hz, 1H), 6.69 (s, 1H), 4.99-4.89 (m, 1H), 4.15 (s, 1H), 3.03 (s, 3H), 2.94 (t, J = 7.4 Hz, 2H), 2.83 (t, J = 7.4 Hz, 2H), 2.04 (p, J = 7.5 Hz, 2H), 1.84-1.72 (m, 2H), 1.64-1.57 (m, 4H), 1.49-1.38 (m, 2H), 1.14 (s, 3H). One exchangeable proton not observed. LCMS m/z 460.3 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R35  5 [00109] .sup.1H NMR (DMSO-d6) δ 8.71 (dd, J = 5.0, 0.8 Hz, 1H), 8.69-8.65 (m, 1H), 8.45- 8.40 (m, 1H), 8.38 (d, J = 1.7 Hz, 1H), 8.03 (s, 1H), 7.97 (td, J = 7.7, 1.8 Hz, 1H), 7.49-7.45 (m, 1H), 7.43 (dd, J = 5.0, 1.8 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 3.02 (s, 3H), 2.98 (t, J = 7.5 Hz, 2H), 2.85 (t, J = 7.4 Hz, 2H), 2.07 (p, J = 7.5 Hz, 2H). One proton not observed. LCMS m/z 409.2 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R4  6 [00110] .sup.1H NMR (DMSO-d6) δ 8.17 (d, J = 5.2 Hz, 1H), 7.97 (s, 1H), 7.24 (d, J = 7.7 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 6.94 (dd, J = 5.3, 1.5 Hz, 1H), 6.76 (s, 1H), 5.26-5.18 (m, 1H), 3.06 (s, 3H), 2.95 (t, J = 7.4 Hz, 2H), 2.82 (t, J = 7.4 Hz, 2H), 2.16-1.94 (m, 8H), 1.90-1.80 (m, 2H). One exchangeable proton not observed. LCMS m/z 466.2 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R24  7 [00111] .sup.1H NMR (DMSO-d6) δ 8.68 (d, J = 5.1, 0.8 Hz, 1H), 8.05 (s, 1H), 7.49-7.43 (m, 2H), 7.36-7.22 (m, 6H), 3.02-2.93 (m, 5H), 2.84 (t, J = 7.4 Hz, 2H), 2.37 (s, 3H), 2.06 (p, J = 7.5 Hz, 2H). One exchangeable proton not observed. LCMS m/z 422.2 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R7  8 [00112] .sup.1H NMR (DMSO-d6) δ 8.12 (d, J = 5.3 Hz, 1H), 7.59 (s, 1H), 7.17 (d, J = 7.7 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.94 (dd, J = 5.3, 1.4 Hz, 1H), 6.73 (s, 1H), 5.22-5.12 (m, 1H), 3.96-3.89 (m, 1H), 3.57-3.43 (m, 2H), 2.93 (t, J = 7.4 Hz, 2H), 2.87 (s, 3H), 2.82 (t, J = 7.4 Hz, 2H), 2.17-2.10 (m, 1H), 2.07-1.97 (m, 3H), 1.57-1.47 (m, 1H), 1.24 (m, 1H), 1.14 (d, J = 6.2 Hz, 3H). One exchangeable proton not observed. LCMS m/z 446.3 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R18  9 [00113] .sup.1H NMR (DMSO-d6) δ 8.11 (d, J = 5.3 Hz, 1H), 7.65 (s, 1H), 7.18 (d, J = 7.7 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.94 (dd, J = 5.3, 1.5 Hz, 1H), 6.72 (s, 1H), 5.00 (p, J = 7.1 Hz, 1H), 4.64 (s, 2H), 4.54 (s, 2H), 2.98- 2.87 (m, 5H), 2.82 (t, J = 7.4 Hz, 2H), 2.79-2.72 (m, 2H), 2.29-2.20 (m, 2H), 2.02 (p, J = 7.5 Hz, 2H). One exchangeable proton not observed. LCMS m/z 444.3 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R12 10 [00114] .sup.1H NMR (DMSO-d6) δ 8.08 (d, J = 5.3 Hz, 1H), 7.09-7.02 (m, 3H), 6.96 (dd, J = 5.3, 1.5 Hz, 1H), 6.75 (m, 1H), 5.36-5.28 (m, 1H), 3.78-3.71 (m, 1H), 3.70-3.63 (m, 1H), 2.90 (t, J = 7.4 Hz, 2H), 2.84 (t, J = 7.4 Hz, 2H), 2.62 (s, 3H), 2.06-1.96 (m, 4H), 1.54-1.46 (m, 1H), 1.46-1.40 (m, 1H), 1.21 (s, 3H), 1.20 (s, 3H). One exchangeable proton not observed. LCMS m/z 460.3 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R21 11 [00115] .sup.1H NMR (DMSO-d6) δ 8.12 (d, J = 5.3 Hz, 1H), 7.80 (s, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.94 (dd, J = 5.3, 1.4 Hz, 1H), 6.74 (d, J = 1.4 Hz, 1H), 4.92- 4.83 (m, 1H), 2.97 (s, 3H), 2.93 (t, J = 7.5 Hz, 2H), 2.81 (t, J = 7.4 Hz, 2H), 2.70- 2.59 (m, 3H), 2.21 (s, 6H), 2.02 (p, J = 7.5 Hz, 2H), 1.97-1.88 (m, 2H). One exchangeable proton not observed. LCMS m/z 445.3 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R14 12 [00116] .sup.1H NMR (DMSO-d6) δ 8.59 (d, J = 5.1 Hz, 1H), 7.89 (s, 1H), 7.72-7.58 (m, 3H), 7.50- 7.31 (m, 4H), 7.26-7.18 (m, 2H), 2.98- 2.90 (m, 5H), 2.84 (t, J = 7.4 Hz, 2H), 2.09-2.00 (m, 2H). One exchangeable proton not observed. LCMS m/z 432.2 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R8 13 [00117] .sup.1H NMR (DMSO-d6) δ 8.15 (d, J = 5.2 Hz, 1H), 7.90 (s, 1H), 7.23 (d, J = 7.7 Hz, 1H), 7.15 (d, J = 7.7 Hz, 1H), 6.94 (dd, J = 5.3, 1.5 Hz, 1H), 6.75 (s, 1H), 4.14 (d, J = 6.6 Hz, 2H), 3.90-3.83 (m, 2H), 3.03 (s, 3H), 2.94 (t, J = 7.5 Hz, 2H), 2.82 (t, J = 7.4 Hz, 2H), 2.08-1.97 (m, 3H), 1.72-1.63 (m, 2H), 1.41-1.27 (m, 2H). One exchangeable proton not observed. Two protons under H.sub.2O. LCMS m/z 446.3 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R17 14 [00118] .sup.1H NMR (DMSO-d6) δ 8.52 (d, J = 5.0 Hz, 1H), 7.96 (s, 1H), 7.27-7.21 (m, 2H), 7.20- 7.14 (m, 2H), 3.99-3.91 (m, 2H), 3.49- 3.40 (m, 2H), 3.05 (s, 3H), 2.98-2.90 (m, 3H), 2.82 (t, J = 7.4 Hz, 2H), 2.04 (p, J = 7.5 Hz, 2H), 1.84-1.73 (m, 4H). One exchangeable proton not observed. LCMS m/z 416.2 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R6 15 [00119] .sup.1H NMR (DMSO-d6) δ 7.96 (d, J = 5.1 Hz, 1H), 7.41 (s, 1H), 7.16 (d, J = 7.6 Hz, 1H), 6.93 (d, J = 7.5 Hz, 1H), 6.68 (d, J = 5.2 Hz, 1H), 5.17-5.05 (m, 1H), 2.95-2.89 (m, 5H), 2.90-2.83 (m, 1H), 2.82-2.72 (m, 3H), 2.34 (s, 3H), 2.06-1.98 (m, 4H), 1.91 (s, 3H), 1.82-1.73 (m, 2H). One exchangeable proton not observed. Two protons under DMSO. LCMS m/z 459-1 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R55 16 [00120] .sup.1H NMR (DMSO-d6) δ 8.67 (d, J = 5.0 Hz, 1H), 8.14-8.09 (m, 2H), 7.92 (s, 1H), 7.75 (s, 1H), 7.51-7.46 (m, 2H), 7.46-7.42 (m, 1H), 7.34 (dd, J = 5.1, 1.6 Hz, 1H), 7.25- 7.21 (m, 2H), 2.96 (t, J = 7.4 Hz, 2H), 2.88- 2.82 (m, 5H), 2.04 (p, J = 7.5 Hz, 2H). One exchangeable proton not observed. LCMS m/z 408.3 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R5 17 [00121] .sup.1H NMR (DMSO-d6) δ 10.30 (br s, 1H), 8.19 (d, J = 5.3 Hz, 1H), 8.11 (dd, J = 4.9, 2.0 Hz, 1H), 8.04 (s, 1H), 7.53 (m, 1H), 7.25 (d, J = 7.7 Hz, 1H), 7.17 (d, J = 7.7 Hz, 1H), 6.93 (d, J = 5.3 Hz, 1H), 6.87 (d, J = 8.6 Hz, 1H), 6.74 (s, 1H), 6.62 (m, 1H), 5.31-5.22 (m, 1H), 4.07-3.99 (m, 2H), 3.32-3.26 (m, 2H), 3.10 (s, 3H), 2.95 (t, J = 7.5 Hz, 2H), 2.81 (t, J = 7.4 Hz, 2H), 2.10-2.00 (m, 4H), 1.71-1.61 (m, 2H). LCMS m/z 508.3 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R30 18 [00122] .sup.1H NMR (DMSO-d6) δ 8.38 (d, J = 5.3 Hz, 1H), 8.07 (s, 1H), 7.87 (d, J = 7.6 Hz, 2H), 7.63 (d, J = 7.5 Hz, 2H), 7.46 (t, J = 7.5 Hz, 2H), 7.32 (t, J = 7.4 Hz, 2H), 7.25 (m, 2H), 7.20 (d, J = 7.7 Hz, 1H), 7.13-7.07 (m, 1H), 6.85 (s, 1H), 3.04 (s, 3H), 2.95 (t, J = 7.4 Hz, 2H), 2.82 (t, J = 7.4 Hz, 2H), 2.04 (p, J = 7.5 Hz, 2H). One exchangeable proton not observed. LCMS m/z 512.2 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R33 19 [00123] .sup.1H NMR (DMSO-d6) δ 8.14 (d, J = 5.3 Hz, 1H), 7.91 (s, 1H), 7.34-7.31 (m, 4H), 7.28- 7.20 (m, 2H), 7.14 (d, J = 7.6 Hz, 1H), 6.90 (dd, J = 5.3, 1.5 Hz, 1H), 6.72-6.69 (m, 1H), 5.06-5.00 (m, 1H), 3.53 (s, 2H), 3.04 (s, 3H), 2.94 (t, J = 7.4 Hz, 2H), 2.81 (t, J = 7.4 Hz, 2H), 2.77-2.70 (m, 2H), 2.32-2.22 (m, 2H), 2.08-1.95 (m, 4H), 1.73-1.64 (m, 2H). One exchangeable proton not observed. LCMS m/z 521.2 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R31 20 [00124] .sup.1H NMR (DMSO-d6) δ 8.06 (dd, J = 5.1, 0.9 Hz, 1H), 7.51-7.45 (m, 5H), 7.38- 7.29 (m, 5H), 7.27-7.22 (m, 2H), 7.20 (s, 1H), 7.14 (d, J = 7.7 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.98-6.94 (m, 2H), 2.92 (t, J = 7.5 Hz, 2H), 2.85-2.80 (m, 2H), 2.75 (s, 3H), 2.01 (p, J = 7.4 Hz, 2H). LCMS m/z 512.3 (M − H).sup.− (ES.sup.−). Intermediate L1 + Intermediate R32 21 [00125] .sup.1H NMR (DMSO-d6) δ 7.52 (br s, 1H), 7.31 (t, J = 6.9 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 6.98-6.86 (m, 3H), 4.51-4.43 (m, 1H), 3.00 (s, 3H), 2.92 (t, J = 7.4 Hz, 2H), 2.86-2.76 (m, 4H), 2.58-2.52 (m, 2H), 2.35 (s, 3H), 2.07-1.92 (m, 4H), 1.78-1.66 (m, 2H). One exchangeable proton not observed. LCMS m/z 444.3 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R54 22 [00126] .sup.1H NMR (DMSO-d6) δ 8.15 (d, J = 5.3 Hz, 1H), 7.90 (s, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.91 (dd, J = 5.3, 1.5 Hz, 1H), 6.71 (d, J = 1.4 Hz, 1H), 5.02 (tt, J = 8.6, 4.0 Hz, 1H), 3.03 (s, 3H), 2.94 (t, J = 7.4 Hz, 2H), 2.89-2.77 (m, 4H), 2.42 (t, J = 10.5 Hz, 2H), 2.04 (p, J = 7.5 Hz, 2H), 1.99-1.91 (m, 2H), 1.68-1.55 (m, 3H), 0.47-0.38 (m, 2H), 0.36-0.25 (m, 2H). One exchangeable proton not observed. LCMS m/z 471.3 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R25 23 [00127] .sup.1H NMR (DMSO-d6) δ 8.14 (d, J = 5.3 Hz, 1H), 7.64 (s, 1H), 7.35-7.28 (m, 4H), 7.25- 7.20 (m, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.95 (dd, J = 5.3, 1.5 Hz, 1H), 6.75 (d, J = 1.4 Hz, 1H), 4.48 (t, J = 6.9 Hz, 2H), 3.04 (t, J = 6.9 Hz, 2H), 2.93 (t, J = 7.4 Hz, 2H), 2.88 (s, 3H), 2.82 (t, J = 7.4 Hz, 2H), 2.02 (p, J = 7.5 Hz, 2H). One exchangeable proton not observed. LCMS m/z 452.3 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R23 24 [00128] .sup.1H NMR (DMSO-d6) δ 8.13 (d, J = 5.3 Hz, 1H), 7.50 (s, 1H), 7.24-7.18 (m, 2H), 7.15 (d, J = 7.7 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 7.00-6.93 (m, 3H), 6.80-6.74 (m, 2H), 5.18 (tt, J = 8.5, 4.0 Hz, 1H), 3.60- 3.52 (m, 2H), 3.08-3.00 (m, 2H), 2.92 (t, J = 7.4 Hz, 2H), 2.86-2.77 (m, 5H), 2.15- 2.07 (m, 2H), 2.01 (p, J = 7.5 Hz, 2H), 1.81- 1.72 (m, 2H). One exchangeable proton not observed. LCMS m/z 507.3 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R29 25 [00129] .sup.1H NMR (DMSO-d6) δ 8.46 (d, J = 5.1 Hz, 1H), 7.41 (s, 1H), 7.25 (dd, J = 5.1, 1.7 Hz, 1H), 7.15 (d, J = 7.9 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 3.62-3.55 (m, 6H), 2.92 (t, J = 7.5 Hz, 2H), 2.84 (t, J = 7.4 Hz, 2H), 2.75 (s, 3H), 2.44 (d, J = 5.6 Hz, 4H), 2.01 (p, J = 7.4 Hz, 2H). Two exchangeable protons not observed. LCMS m/z 431.3 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R41 26 [00130] .sup.1H NMR (DMSO-d6) δ 8.58-8.52 (m, 2H), 8.12 (d, J = 5.3 Hz, 1H), 7.48 (s, 1H), 7.44-7.42 (m, 2H), 7.15 (d, J = 7.7 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 7.02 (dd, J = 5.3, 1.5 Hz, 1H), 6.95-6.91 (m, 1H), 5.45 (s, 2H), 2.93 (t, J = 7.4 Hz, 2H), 2.84 (t, J = 7.4 Hz, 2H), 2.77 (s, 3H), 2.02 (p, J = 7.5 Hz, 2H). One exchangeable proton not observed. LCMS m/z 439.2 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R13 27 [00131] .sup.1H NMR (DMSO-d6) δ 8.12 (d, J = 5.3 Hz, 1H), 7.52 (s, 1H), 7.16 (d, J = 7.7 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.96 (dd, J = 5.3, 1.4 Hz, 1H), 6.79 (s, 1H), 4.16 (d, J = 6.0 Hz, 2H), 3.05 (d, J = 11.5 Hz, 2H), 2.92 (t, J = 7.4 Hz, 2H), 2.86-2.79 (m, 5H), 2.42 (s, 3H), 2.39-2.31 (m, 2H), 2.02 (p, J = 7.5 Hz, 2H), 1.88-1.75 (m, 3H), 1.48- 1.36 (m, 2H). One exchangeable proton not observed. LCMS m/z 459.2 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R20 28 [00132] .sup.1H NMR (DMSO-d6) δ 7.95 (d, J = 5.2 Hz, 1H), 7.42 (s, 1H), 7.14 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.48-6.43 (m, 2H), 6.40 (d, J = 7.4 Hz, 1H), 3.81-3.72 (m, 1H), 2.99-2.88 (m, 7H), 2.82 (t, J = 7.4 Hz, 2H), 2.46-2.40 (m, 2H), 2.38 (s, 3H), 2.05-1.98 (m, 2H), 1.98-1.91 (m, 2H), 1.59-1.48 (m, 2H). One exchangeable proton not observed. LCMS m/z 444.2 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R42 29 [00133] .sup.1H NMR (DMSO-d6) δ 8.11 (d, J = 5.3 Hz, 1H), 7.52 (s, 1H), 7.16 (d, J = 7.7 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.94 (dd, J = 5.3, 1.5 Hz, 1H), 6.72 (d, J = 1.4 Hz, 1H), 4.98- 4.87 (m, 1H), 2.92 (t, J = 7.4 Hz, 2H), 2.87- 2.77 (m, 5H), 2.74-2.67 (m, 1H), 2.47 (s, 6H), 2.22-2.13 (m, 2H), 2.02 (p, J = 7.5 Hz, 2H), 1.98-1.88 (m, 2H), 1.56-1.34 (m, 4H). One exchangeable proton not observed. LCMS m/z 473.4 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R27 30 [00134] .sup.1H NMR (DMSO-d6) δ 8.16 (d, J = 5.3 Hz, 1H), 7.93 (s, 1H), 7.42-7.29 (m, 5H), 7.23 (d, J = 7.7 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.93 (dd, J = 5.3, 1.5 Hz, 1H), 6.74 (d, J = 1.4 Hz, 1H), 5.25-5.17 (m, 1H), 5.10 (s, 2H), 3.83-3.74 (m, 2H), 3.04 (s, 3H), 2.94 (t, J = 7.4 Hz, 2H), 2.81 (t, J = 7.4 Hz, 2H), 2.08-1.95 (m, 4H), 1.67-1.53 (m, 2H). One exchangeable proton not observed. Two aliphatic protons obscured by solvent. LCMS m/z 565.0 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R34 31 [00135] .sup.1H NMR (DMSO-d6) δ 8.15 (d, J = 5.2 Hz, 1H), 7.85 (s, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 5.3 Hz, 1H), 6.73 (s, 1H), 5.11 (d, J = 5.8 Hz, 1H), 3.05-2.87 (m, 6H), 2.82 (t, J = 7.5 Hz, 2H), 2.64 (s, 1H), 2.37-2.14 (m, 5H), 2.08-1.99 (m, 2H), 1.99-1.81 (m, 1H), 1.81-1.73 (m, 1H), 1.63-1.52 (m, 1H), 1.52-1.41 (m, 1H). One exchangeable proton not observed. LCMS m/z 445.4 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R15 32 [00136] .sup.1H NMR (DMSO-d6) δ 8.16 (d, J = 5.3 Hz, 1H), 7.91 (s, 1H), 7.23 (d, J = 7.7 Hz, 1H), 7.15 (d, J = 7.7 Hz, 1H), 6.94 (dd, J = 5.3, 1.5 Hz, 1H), 6.74 (s, 1H), 5.26-5.19 (m, 1H), 3.95-3.89 (m, 1H), 3.70 (m, 1H), 3.21 (t, J = 9.7 Hz, 1H), 3.04 (s, 3H), 2.95 (t, J = 7.5 Hz, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.08-1.99 (m, 6H), 1.98-1.91 (m, 1H), 1.69-1.60 (m, 1H), 1.57-1.48 (m, 1H). One exchangeable proton not observed. One proton under DMSO. LCMS m/z 473.4 (M + H)+ (ES+). Intermediate L1 + Intermediate R26 33 [00137] .sup.1H NMR (DMSO-d6) δ 8.15 (d, J = 5.2 Hz, 1H), 7.91 (s, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H), 6.92 (d, J = 5.3 Hz, 1H), 6.73 (s, 1H), 5.23-5.15 (m, 1H), 3.90-3.82 (m, 2H), 3.53-3.45 (m, 2H), 3.03 (s, 3H), 2.94 (t, J = 7.5 Hz, 2H), 2.81 (t, J = 7.3 Hz, 2H), 2.08-1.97 (m, 4H), 1.69-1.58 (m, 2H). One exchangeable proton not observed. LCMS m/z 432.4 (M + H)+ (ES+). Intermediate L1 + Intermediate R9 34 [00138] .sup.1H NMR (DMSO-d6) δ 8.20-8.17 (m, 1H), 7.89 (s, 1H), 7.50-7.45 (m, 2H), 7.41- 7.36 (m, 2H), 7.35-7.31 (m, 1H), 7.23 (d, J = 7.7 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.98 (dd, J = 5.3, 1.5 Hz, 1H), 6.84 (d, J = 1.4 Hz, 1H), 5.38 (s, 2H), 2.98 (s, 3H), 2.94 (t, J = 7.4 Hz, 2H), 2.82 (t, J = 7.4 Hz, 2H), 2.04 (p, J = 7.5 Hz, 2H). One exchangeable proton not observed. LCMS m/z 438.2 (M + H)+ (ES+). Intermediate L1 + Intermediate R19 35 [00139] .sup.1H NMR (DMSO-d6) δ 8.13 (d, J = 5.3 Hz, 1H), 7.63 (s, 1H), 7.18 (d, J = 7.7 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.94 (dd, J = 5.3, 1.5 Hz, 1H), 6.75 (d, J = 1.5 Hz, 1H), 5.09- 5.00 (m, 1H), 2.97-2.88 (m, 5H), 2.82 (t, J = 7.5 Hz, 4H), 2.47-2.38 (m, 2H), 2.34 (s, 3H), 2.02 (p, J = 7.3 Hz, 4H), 1.79- 1.69 (m, 2H). One exchangeable proton not observed. LCMS m/z 445.2 (M + H)+ (ES+). Intermediate L1 + Intermediate R16 36 [00140] .sup.1H NMR (DMSO-d6) δ 8.08 (d, J = 5.2 Hz, 1H), 7.44-7.38 (m, 2H), 7.21-7.12 (m, 5H), 7.09 (s, 2H), 7.02 (s, 1H), 2.91 (t, J = 7.4 Hz, 2H), 2.86 (t, J = 7.4 Hz, 2H), 2.60 (s, 3H), 2.00 (p, J = 7.5 Hz, 2H). One exchangeable proton not observed. LCMS m/z 424.3 (M + H)+ (ES+). Intermediate L1 + Intermediate R11 37 [00141] .sup.1H NMR (DMSO-d6) δ 8.07 (d, J = 5.3 Hz, 1H), 7.10-7.02 (m, 3H), 6.97 (dd, J = 5.3, 1.5 Hz, 1H), 6.78 (s, 1H), 5.03-4.97 (m, 1H), 3.91-3.85 (m, 1H), 3.67-3.61 (m, 1H), 3.53-3.45 (m, 2H), 2.90 (t, J = 7.3 Hz, 2H), 2.84 (t, J = 7.4 Hz, 2H), 2.60 (s, 3H), 2.10-2.03 (m, 1H), 1.99 (p, J = 7.5 Hz, 2H), 1.84-1.70 (m, 2H), 1.60-1.50 (m, 1H). One exchangeable proton not observed. LCMS m/z 432.2 (M + H)+ (ES+). Intermediate L1 + Intermediate R10 38 [00142] .sup.1H NMR (DMSO-d6) δ 8.15 (d, J = 5.3 Hz, 1H), 7.78 (s, 1H), 7.33 (dd, J = 8.8, 3.0 Hz, 1H), 7.22 (dd, J = 9.2, 3.0 Hz, 1H), 7.04- 6.97 (m, 1H), 6.84 (s, 1H), 5.12-5.02 (m, 1H), 2.94-2.85 (m, 2H), 2.81 (s, 3H), 2.40 (s, 3H), 2.09 (s, 3H), 2.07-1.97 (m, 2H), 1.82-1.71 (m, 2H). Two protons masked by DMSO and one exchangeable proton not observed. LCMS m/z 461.3 (M + H)+ (ES+). Intermediate L1 + Intermediate R43 39 [00143] .sup.1H NMR (DMSO-d6) δ 8.20-8.08 (m, 1H), 7.78-7.62 (m, 1H), 7.23-7.12 (m, 1H), 7.09-6.90 (m, 2H), 6.90-6.73 (m, 1H), 5.12-4.98 (m, 1H), 5.65-3.54 (m, 2H), 2.92-2.69 (m, 5H), 2.41-2.29 (m, 3H), 2.10-1.95 (m, 2H), 1.83-1.55 (m, 8H), 1.39-1.18 (m, 5H). One exchangeable proton not observed. LCMS m/z 505.3 (M + H)+ (ES+). Intermediate L1 + Intermediate R51 40 [00144] .sup.1H NMR (DMSO-d6) δ 8.14 (d, J = 5.3 Hz, 1H), 7.69 (s, 1H), 7.17-7.11 (m, 1H), 7.11- 7.04 (m, 1H), 7.04-6.96 (m, 1H), 6.83 (s, 1H), 5.11-5.02 (m, 1H), 2.93-2.80 (m, 5H), 2.48-2.44 (m, 2H), 2.39 (s, 3H), 2.07-1.98 (m, 2H), 1.93-1.83 (m, 1H), 1.82-1.70 (m, 2H), 0.88 (d, J = 6.6 Hz, 6H). Two protons behind DMSO peak and one exchangeable proton not observed. LCMS m/z 479.0 (M + H)+ (ES+). Intermediate L1 + Intermediate R44 41 [00145] .sup.1H NMR (DMSO-d6) δ 8.15 (d, J = 5.3 Hz, 1H), 7.68 (br s, 1H), 7.20 (m, 1H), 7.10- 6.92 (m, 2H), 6.82 (s, 1H), 5.11-5.02 (m, 1H), 3.26-3.10 (m, 2H), 2.94-2.79 (m, 4H), 2.67-2.52 (m, 2H), 2.41 (s, 3H), 2.11- 1.90 (m, 4H), 1.86-1.68 (m, 4H), 1.67- 1.57 (m, 2H), 1.55-1.45 (m, 2H). One exchangeable proton not observed. LCMS m/z 491.3 (M + H)+ (ES+). Intermediate L1 + Intermediate R50 42 [00146] .sup.1H NMR (DMSO-d6) δ 8.17 (d, J = 5.2 Hz, 1H), 7.69 (s, 1H), 7.56-7.31 (m, 5H), 7.26 (m, 2H), 7.05 (d, J = 5.4 Hz, 1H), 6.91 (s, 1H), 5.12-5.01 (m, 1H), 2.95-2.82 (m, 2H), 2.67-2.51 (m, 5H), 2.39 (s, 3H), 2.08-1.98 (m, 2H), 1.82-1.71 (m, 2H). One exchangeable proton not observed. LCMS m/z 499.3 (M + H)+ (ES+). Intermediate L1 + Intermediate R52 43 [00147] .sup.1H NMR (DMSO-d6) δ 8.14 (d, J = 5.2 Hz, 1H), 7.71-7.51 (m, 1H), 7.20 (d, J = 9.8 Hz, 1H), 7.07-6.93 (m, 2H), 6.82 (s, 1H), 5.14-4.93 (m, 1H), 3.26-3.09 (m, 1H), 2.94-2.70 (m, 3H), 2.41-2.24 (m, 2H), 2.12-1.87 (m, 2H), 1.82-1.60 (m, 2H), 1.16 (d, J = 6.8 Hz, 6H). 5H under DMSO. One exchangeable proton not observed. LCMS m/z 465.3 (M + H)+ (ES+). Intermediate L1 + Intermediate R45 44 [00148] .sup.1H NMR (DMSO-d6) δ 8.24 (d, J = 5.1 Hz, 1H), 7.46 (s, 1H), 7.10 (s, 1H), 6.79 (dd, J = 5.2, 1.4 Hz, 1H), 6.63 (d, J = 1.2 Hz, 1H), 4.21 (tt, J = 6.3, 3.1 Hz, 1H), 3.02 (s, 3H), 2.90 (t, J = 7.5 Hz, 2H), 2.78-2.71 (m, 2H), 2.05-1.95 (m, 5H), 0.80-0.64 (m, 4H). One exchangeable proton not observed. LCMS m/z 402.3 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R57 45 [00149] .sup.1H NMR (DMSO-d6) δ 8.17 (t, J = 5.7 Hz, 1H), 7.35 (s, 1H), 7.08 (d, J = 5.1 Hz, 1H), 6.72 (td, J = 5.1, 2.6 Hz, 1H), 6.54 (d, J = 5.1 Hz, 1H), 5.03 (s, 1H), 3.00-2.94 (m, 3H), 2.92-2.87 (m, 2H), 2.84-2.78 (m, 2H), 2.75 (s, 2H), 2.38 (s, 2H), 2.34-2.28 (m, 3H), 2.08-1.93 (m, 7H), 1.74 (s, 2H). One exchangeable proton not observed. LCMS m/z 459.4 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R60 46 [00150] .sup.1H NMR (DMSO-d6) δ 8.16 (d, J = 5.2 Hz, 1H), 7.17 (bs, 1H), 7.04 (s, 1H), 6.71 (dd, J = 5.2, 1.4 Hz, 1H), 6.51 (s, 1H), 4.97-4.88 (m, 1H), 2.95-2.82 (m, 5H), 2.79-2.72 (m, 2H), 2.66-2.59 (m, 1H), 2.42 (s, 6H), 2.21- 2.15 (m, 2H), 2.04-1.87 (m, 7H), 1.53-1.38 (m, 4H). One exchangeable proton not observed. LCMS m/z 487.4 (M + H)+ (ES.sup.+); m/z 485.3 (M − H).sup.− (ES.sup.−). Intermediate L1 + Intermediate R64 47 [00151] .sup.1H NMR (DMSO-d6) δ 8.17 (d, J = 5.1 Hz, 1H), 7.25 (s, 1H), 7.07 (s, 1H), 6.75 (d, J = 5.2 Hz, 1H), 6.59 (s, 1H), 4.33-4.01 (m, 2H), 3.08-2.97 (m, 1H), 2.95-2.82 (m, 6H), 2.76 (t, J = 7.6 Hz, 2H), 2.42-2.30 (m, 3H), 2.26-2.04 (m, 2H), 2.04-1.93 (m, 6H), 1.78-1.66 (m, 2H), 1.63-1.50 (m, 1H), 1.16-1.04 (m, 1H). One exchangeable proton not observed. LCMS m/z 473.0 (M+H).sup.+ (ES.sup.+); m/z 471.2 (M − H).sup.− (ES.sup.−). Intermediate L1 + Intermediate R62 48 [00152] .sup.1H NMR (DMSO-d6) δ 8.14 (d, J = 5.2 Hz, 1H), 7.14 (s, 1H), 7.05 (s, 1H), 6.74-6.68 (m, 1H), 6.52 (s, 1H), 5.05 (tt, J = 7.1, 3.4 Hz, 1H), 4.47 (d, J = 3.9 Hz, 1H), 3.68- 3.60 (m, 1H), 3.17 (d, J = 3.3 Hz, 1H), 2.92- 2.84 (m, 4H), 2.76 (s, 1H), 2.03-1.94 (m, 5H), 1.92-1.83 (m, 2H), 1.72-1.64 (m, 3H), 1.60 (dd, J = 7.7, 4.1 Hz, 4H). One exchangeable proton not observed. LCMS m/z 460.4 (M+H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R61 49 [00153] .sup.1H NMR (DMSO-d6) δ 8.18 (d, J = 5.2 Hz, 1H), 7.38 (s, 1H), 7.09 (s, 1H), 6.73 (dd, J = 5.2, 1.4 Hz, 1H), 6.56 (d, J = 1.4 Hz, 1H), 5.25-5.16 (m, 1H), 3.93-3.83 (m, 2H), 3.54-3.46 (m, 2H), 2.97 (s, 3H), 2.90 (t, J = 7.4 Hz, 2H), 2.81-2.68 (m, 2H), 2.09- 1.96 (m, 7H), 1.72-1.59 (m, 2H). One exchangeable proton not observed. LCMS m/z 446.2 (M+H).sup.+ (ES.sup.+); m/z 444.2 (M − H).sup.− (ES.sup.−). Intermediate L1 + Intermediate R59 50 [00154] .sup.1H NMR (DMSO-d6) δ 8.19 (d, J = 5.2 Hz, 1H), 7.46 (bs, 1H), 7.10 (s, 1H), 6.72 (dd, J = 5.2, 1.4 Hz, 1H), 6.52 (s, 1H), 5.04-4.95 (m, 1H), 2.90 (t, J = 7.4 Hz, 2H), 2.77- 2.69 (m, 4H), 2.64 (s, 6H), 2.28-2.16 (m, 5H), 2.09-1.94 (m, 7H), 1.73-1.64 (m, 2H). One exchangeable proton not observed. LCMS m/z 488.4 (M+H).sup.+ (ES.sup.+); m/z 486.3 (M − H).sup.− (ES.sup.−). Intermediate L3 + Intermediate R60 51 [00155] .sup.1H NMR (DMSO-d6) δ 9-94 (s, 1H), 8.18 (d, J = 5.2 Hz, 1H), 7.46 (s, 1H), 7.09 (s, 1H), 6.73 (dd, J = 5.2, 1.4 Hz, 1H), 6.54 (s, 1H), 5.02 (tt, J = 8.7, 4.1 Hz, 1H), 2.90 (t, J = 7.4 Hz, 2H), 2.83-2.69 (m, 5H), 2.37- 2.24 (m, 5H), 2.07-1.97 (m, 7H), 1.77- 1.66 (m, 2H), 0.97-0.86 (m, 4H). LCMS m/z 485.1 (M + H).sup.+ (ES.sup.+). Intermediate L2 + Intermediate R60 52 [00156] .sup.1H NMR (DMSO-d6) δ 8.00 (d, J = 5.0 Hz, 1H), 7.07 (s, 2H), 6.59 (d, J = 5.2 Hz, 1H), 5.15-5.06 (m, 1H), 2.95-2.88 (m, 5H), 2.82-2.68 (m, 4H), 2.45-2.37 (m, 2H), 2.30 (s, 3H), 2.05-1.96 (m, 4H), 1.88 (s, 3H), 1.80-1.71 (m, 5H). One exchangeable proton not observed. LCMS m/z 473.4 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R63 53 [00157] .sup.1H NMR (DMSO-d6) δ 8.18 (d, J = 5.2 Hz, 1H), 7.37 (s, 1H), 7.08 (s, 1H), 6.75 (dd, J = 5.2, 1.4 Hz, 1H), 6.58 (s, 1H), 5.56-5.49 (m, 1H), 3.96-3.89 (m, 1H), 3.89-3.83 (m, 1H), 3.83-3.73 (m, 2H), 2.96 (s, 3H), 2.90 (t, J = 7.4 Hz, 2H), 2.80-2.70 (m, 2H), 2.29-2.20 (m, 1H), 2.07-1.95 (m, 6H). One exchangeable proton not observed. LCMS m/z 432.2 (M + H).sup.+ (ES.sup.+); m/z 430.1 (M − H).sup.− (ES.sup.−). Intermediate L1 + Intermediate R58 54 [00158] .sup.1H NMR (DMSO-d6) δ 8.14 (dd, J = 5.1, 1.8 Hz, 1H), 7.02 (s, 1H), 6.70 (dd, J = 5.2, 1.4 Hz, 1H), 6.52 (d, J = 1.4 Hz, 1H), 5.06 (s, 1H), 3.24 (s, 3H), 2.88 (t, J = 7.4 Hz, 2H), 2.84-2.72 (m, 5H), 2.03-1.94 (m, 5H), 1.83-1.69 (m, 5H), 1.67-1.59 (m, 2H). Two protons masked by water, two exchangeable protons not observed. LCMS m/z 474.4 (M + H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R66 55 [00159] .sup.1H NMR (DMSO-d6) δ 8.30-8.04 (m, 1H), 6.97 (d, J = 7.8 Hz, 2H), 6.70 (dd, J = 5.2, 1.4 Hz, 1H), 6.54-6.49 (m, 1H), 5.02- 4.95 (m, 1H), 3.25 (s, 3H), 2.86 (t, J = 7.5 Hz, 2H), 2.80-2.73 (m, 2H), 2.72-2.62 (m, 3H), 2.11-2.03 (m, 2H), 2.02-1.92 (m, 7H), 1.82-1.69 (m, 1H), 1.63 (s, 1H), 1.52-1.43 (m, 2H), 1.39-1.31 (m, 1H). One exchangeable proton not observed. LCMS m/z 474.3 (M+H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R66 56 [00160] .sup.1H NMR (DMSO-d6) δ 8.10 (d, J = 5.2 Hz, 1H), 7.74-7.69 (m, 2H), 7.55-7.50 (m, 1H), 7.48 (dd, J = 8.2, 6.5 Hz, 2H), 7.26- 7.17 (m, 1H), 7.00 (s, 1H), 6.61 (dd, J = 5.2, 1.4 Hz, 1H), 6.51 (s, 1H), 5.12 (dq, J = 8.5, 4.2 Hz, 1H), 3.08-3.00 (m, 2H), 2.83 (t, J = 7.5 Hz, 2H), 2.78-2.67 (m, 2H), 2.14-2.04 (m, 2H), 1.96 (s, 3H), 1.94- 1.87 (m, 2H), 1.87-1.80 (m, 2H). Five protons under DMSO. One exchangeable proton not observed. LCMS m/z 521.2 (M+H).sup.+ (ES.sup.+). Intermediate L4 + Intermediate R60 57 [00161] .sup.1H NMR (DMSO-d6) δ 8.16 (d, J = 5.2 Hz, 1H), 7.31 (s, 1H), 7.07 (s, 1H), 6.70 (dd, J = 5.2, 1.4 Hz, 1H), 6.50 (s, 1H), 5.05-4.96 (m, 1H), 2.96 (s, 3H), 2.89 (t, J = 7.5 Hz, 2H), 2.79-2.72 (m, 2H), 2.05-1.96 (m, 7H), 1.78-1.71 (m, 2H), 1.60-1.53 (m, 1H), 1.51-1.32 (m, 4H), 1.31-1.20 (m, 1H). One exchangeable proton not observed. LCMS m/z 444.3 (M+H).sup.+ (ES.sup.+). Intermediate L1 + Intermediate R65 58 [00162] .sup.1H NMR (DMSO-d6) δ 8.16 (d, J = 5.2 Hz, 1H), 7.71 (s, 1H), 7.09 (s, 1H), 6.70 (dd, J = 5.2, 1.4 Hz, 1H), 6.51 (d, J = 1.2 Hz, 1H), 5.01 (tt, J = 8.8, 4.1 Hz, 1H), 2.89 (t, J = 7.5 Hz, 2H), 2.80-2.68 (m, 4H), 2.36- 2.20 (m, 5H), 2.07-1.88 (m, 7H), 1.76- 1.65 (m, 2H), 1.17 (s, 9H). One exchangeable proton not observed. LCMS m/z 501.3 (M+H).sup.+ (ES.sup.+). Intermediate L5 + Intermediate R60

Example 59: N-((5-(2-((1-Allylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)prop-2-ene-1-sulfonamide

[0474] ##STR00163##

[0475] Prop-2-ene-1-sulfonamide (0.09 g, 0.542 mmol) was dissolved in THF (2 mL), and 2M sodium tert-butoxide in THF (0.298 mL, 0.596 mmol) was added. After 30 minutes, 2-((1-allylpiperidin-4-yl)oxy)-4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (Intermediate R.sup.39) (0.30 g, 0.559 mmol) in THF (3 mL) was added. The reaction mixture was stirred at room temperature for 18 hours, concentrated to dryness and purified by basic prep HPLC (20-50% MeCN in water) to afford the title compound (85 mg, 31%) as a white solid.

[0476] .sup.1H NMR (DMSO-d6) δ 10.17 (br s, 1H), 8.14 (d, J=5.3 Hz, 1H), 7.84 (br s, 1H), 7.22 (d, J=7.7 Hz, 1H), 7.12 (d, J=7.7 Hz, 1H), 6.90 (dd, J=5.2, 1.5 Hz, 1H), 6.71 (s, 1H), 5.84 (ddt, J=16.8, 10.1, 6.5 Hz, 1H), 5.72 (ddt, J=17.3, 10.1, 7.3 Hz, 1H), 5.39-5.13 (m, 4H), 5.10-4.99 (m, 1H), 3.97 (d, J=7.3 Hz, 2H), 3.15-3.01 (m, 2H), 2.94 (t, J=7.5 Hz, 2H), 2.80 (t, J=7.5 Hz, 4H), 2.43-2.27 (m, 2H), 2.11-1.94 (m, 4H), 1.77-1.64 (m, 2H).

[0477] LCMS m/z 497.3 (M+H).sup.+ (ES.sup.+).

[0478] The following examples were prepared according to the general procedure of Example 59:

TABLE-US-00012 Ex. Structure and name Characterisation and procedure 60 [00164] .sup.1H NMR (DMSO-d6) δ 9.69 (bs, 1H), 8.15 (d, J = 5.2 Hz, 1H), 7.44 (s, 1H), 7.14-6.99 (m, 1H), 6.98 (s, 1H), 6.72 (d, J = 5.1 Hz, 1H), 6.67-6.55 (m, 2H), 5.22-5.12 (m, 1H), 4.95 (s, 1H), 3.22 (s, 2H), 3.11-2.94 (m, 2H), 2.85 (t, J = 7.5 Hz, 2H), 2.72-2.61 (m, 5H), 2.17-2.07 (m, 2H), 2.00-1.88 (m, 7H), 1.37 (s, 6H). LCMS m/z 569.3 (M + H).sup.+ (ES.sup.+). Intermediate R40 + known sulfonamide 61 [00165] .sup.1H NMR (DMSO-d6) δ 8.15 (d, J = 5.1 Hz, 1H), 7.37-7.22 (m, 1H), 7.06 (s, 1H), 6.74- 6.67 (m, 1H), 6.52 (s, 1H), 5.07-4.95 (m, 1H), 3.22-3.17 (m, 1H), 3.08-2.98 (m, 2H), 2.89 (t, J = 7.5 Hz, 2H), 2.82-2.70 (m, 4H), 2.26 (s, 5H), 2.07-1.94 (m, 9H), 1.85-1.66 (m, 5H), 1.62-1.52 (m, 2H), 1.04 (t, J = 7.1 Hz, 3H). One exchangeable proton not observed, one proton under DMSO. LCMS m/z 556.3 (M + H).sup.+ (ES.sup.+). Intermediate R40 + known sulfonamide 62 [00166] .sup.1H NMR (DMSO-d6) δ 8.16-8.10 (m, 1H), 7.86-7.80 (m, 1H), 7.30 (s, 1H), 7.02 (s, 1H), 6.67 (dd, J = 5.2, 1.6 Hz, 1H), 6.53 (s, 1H), 6.46 (d, J = 2.3 Hz, 1H), 5.11-5.04 (m, 1H), 4.59-4.50 (m, 1H), 3.00-2.89 (m, 2H), 2.85 (t, J = 7.5 Hz, 2H), 2.59-2.53 (m, 4H), 2.42 (s, 3H), 2.11-2.03 (m, 2H), 1.97 (s, 3H), 1.91 (p, J = 7.7 Hz, 2H), 1.86-1.75 (m, 2H), 1.42 (d, J = 6.6 Hz, 6H). One exchangeable proton not observed. LCMS m/z 553.3 (M + H).sup.+ (ES.sup.+). Intermediate R40 + known sulfonamide 63 [00167] .sup.1H NMR (DMSO-d6) δ 8.13 (d, J = 5.3 Hz, 1H), 7.79 (s, 1H), 7.25 (s, 1H), 7.02 (s, 1H), 6.67 (d, J = 5.3 Hz, 1H), 6.53 (s, 1H), 6.47- 6.40 (m, 1H), 5.13-5.04 (m, 1H), 4.23 (t, J = 6.6 Hz, 2H), 2.96-2.89 (m, 2H), 2.85 (t, J = 7.4 Hz, 2H), 2.66 (t, J = 6.6 Hz, 2H), 2.62-2.56 (m, 4H), 2.41 (s, 3H), 2.19 (s, 6H), 2.10-2.03 (m, 2H), 1.98 (s, 3H), 1.96- 1.90 (m, 2H), 1.87-1.73 (m, 2H). One exchangeable proton not observed. LCMS m/z 582.3 (M + H).sup.+ (ES.sup.+). Intermediate R40 + known sulfonamide

Example 64: N-((5-(2-Cyclopropoxypyridin-4-yl)-2,3-dihydrobenzofuran-4-yl)carbamoyl)-1-(1-(dimethylamino)-2-methylpropan-2-yl)-1H-pyrazole-3-sulfonamide, sodium salt

[0479] ##STR00168##

[0480] 5-(2-Cyclopropoxypyridin-4-yl)-2,3-dihydrobenzofuran-4-amine (Intermediate R.sup.53) (150 mg, 0.447 mmol) was dissolved in DCM (3 mL). Saturated aq NaHCO.sub.3 (2 mL) was added, followed by a solution of triphosgene (55 mg, 0.185 mmol) in DCM (1 mL). The mixture was stirred for 1 hour at room temperature. The organic phase was separated by passing through a hydrophobic frit and concentrated in vacuo to give 2-cyclopropoxy-4-(4-isocyanato-2,3-dihydrobenzofuran-5-yl)pyridine as a colourless oil. 1-(1-(Dimethylamino)-2-methylpropan-2-yl)-1H-pyrazole-3-sulfonamide (110 mg, 0.447 mmol) was dissolved in dry THF (2 mL). Sodium tert-butoxide (2M in THF) (250 μL, 0.500 mmol) was added and the mixture was stirred for 30 minutes. A solution of the previously prepared isocyanate in THF (2 mL) was added via syringe and the mixture was stirred at room temperature overnight. The THF was removed in vacuo and the residue was dissolved in DMSO (2 mL) and purified by basic prep HPLC (10-40% MeCN in water). After concentration of product containing fractions, the free acid (75 mg) was isolated as a colourless solid. This solid was dissolved in 0.1 M aq NaOH (1.39 mL, 0.139 mmol) and the solution was freeze dried, giving the title compound (73 mg, 29%) as a colourless solid.

[0481] .sup.1H NMR (DMSO-d6) δ 8.12-8.06 (m, 1H), 7.72-7.65 (m, 1H), 7.47-7.37 (m, 1H), 7.02 (d, J=8.2 Hz, 1H), 6.96-6.93 (m, 1H), 6.83 (s, 1H), 6.61 (d, J=8.4, 3.4 Hz, 1H), 6.35-6.30 (m, 1H), 4.49 (t, J=8.8 Hz, 2H), 4.22-4.17 (m, 1H), 3.04 (t, J=8.8 Hz, 2H), 1.92 (s, 6H), 1.48 (s, 6H), 0.81-0.64 (m, 4H). One CH.sub.2 signal obscured by DMSO peak.

[0482] LCMS m/z 541.2 (M+H).sup.+ (ES.sup.+).

[0483] The following examples were prepared according to the general procedure of Example 64:

TABLE-US-00013 Ex. Structure and name Characterisation and procedure 65 [00169] .sup.1H NMR (DMSO-d6) δ 8.09 (d, J = 5.2 Hz, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.38 (s, 1H), 7.07 (d, J = 7.7 Hz, 1H), 7.04 (d, J = 7.7 Hz, 1H), 6.97 (dd, J = 5.3, 1.4 Hz, 1H), 6.86 (s, 1H), 6.30 (d, J = 2.3 Hz, 1H), 4.20 (tt, J = 6.3, 3.1 Hz, 1H), 2.95 (t, J = 7.0 Hz, 4H), 2.87 (t, J = 7.4 Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H), 2.65 (s, 2H), 1.93 (p, J = 7.5 Hz, 2H), 1.82 (p, J = 7.0 Hz, 2H), 1.45 (s, 6H), 0.80-0.73 (m, 2H), 0.72-0.65 (m, 2H). LCMS m/z 551.1 (M + H).sup.+ (ES.sup.+). Intermediate R48 + known sulfonamide 66 [00170] .sup.1H NMR (DMSO-d6) δ 8.09 (d, J = 5.3 Hz, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.37 (s, 1H), 7.08 (d, J = 7.7 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.97 (dd, J = 5.2, 1.4 Hz, 1H), 6.86 (d, J = 1.4 Hz, 1H), 6.32 (d, J = 2.3 Hz, 1H), 4.20 (tt, J = 6.2, 3.1 Hz, 1H), 2.87 (t, J = 7.4 Hz, 2H), 2.71 (t, J = 7.4 Hz, 2H), 2.53 (s, 2H), 1.94 (s, 8H), 1.49 (s, 6H), 0.81-0.74 (m, 2H), 0.70-0.64 (m, 2H). LCMS m/z 539.1 (M + H).sup.+ (ES.sup.+). Intermediate R48 + known sulfonamide 67 [00171] .sup.1H NMR (DMSO-d6) δ 8.06 (d, J = 5.2 Hz, 1H), 7.74 (d, J = 2.3 Hz, 1H), 7.42 (s, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.92 (dd, J = 5.2, 1.5 Hz, 1H), 6.81 (s, 1H), 6.60 (d, J = 8.2 Hz, 1H), 6.33 (d, J = 2.3 Hz, 1H), 4.89- 4.75 (m, 1H), 4.49 (t, J = 8.8 Hz, 2H), 4.26-4.09 (m, 1H), 3.04 (t, J = 8.8 Hz, 2H), 2.48-2.40 (m, 2H), 2.38-2.28 (m, 2H), 1.83-1.69 (m, 2H), 0.78-0.71 (m, 2H), 0.71-0.63 (m, 2H). LCMS m/z 496.1 (M + H).sup.+ (ES.sup.+). Intermediate R53 + known sulfonamide

Example 68: i-Isopropyl-N-((5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1H-pyrazole-3-sulfonamide, Sodium Salt

[0484] ##STR00172##

[0485] 5-(2-((1-Methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate R.sup.16) (60 mg, 0.186 mmol) and (4-(dimethylamino)pyridin-1-ium-1-carbonyl)((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)amide (60 mg, 0.178 mmol) were suspended in MeCN (2 mL) and stirred at 50° C. for 1 hour. The reaction mixture was purified directly by basic prep HPLC (10-40% MeCN in water). After concentration of product containing fractions, the free acid (55 mg) was isolated as a colourless solid. This solid was dissolved in 0.1 M aq NaOH (1.02 mL, 1 eq). The mixture was freeze dried overnight to give the title compound (50 mg, 50%) as a colourless solid.

[0486] .sup.1H NMR (DMSO-d6) δ 7.99 (d, J=5.3 Hz, 1H), 7.69 (s, 1H), 7.37 (s, 1H), 7.06 (d, J=7.7 Hz, 1H), 7.02 (d, J=7.6 Hz, 1H), 6.87 (d, J=5.2 Hz, 1H), 6.69 (s, 1H), 6.31 (s, 1H), 5.03-4.93 (m, 1H), 4.49 (sept, J=6.8 Hz, 1H), 2.87 (t, J=7.5 Hz, 2H), 2.75-2.61 (m, 4H), 2.19 (s, 3H), 2.14 (t, J=10.8 Hz, 2H), 2.03-1.97 (m, 2H), 1.93 (p, J=7.5 Hz, 2H), 1.73-1.64 (m, 2H), 1.40 (d, J=6.7 Hz, 6H).

[0487] LCMS m/z 539.2 (M+H).sup.+ (ES.sup.+); 537.3 (M−H).sup.− (ES.sup.−).

[0488] The following examples were prepared according to the general procedure of Example 68:

TABLE-US-00014 Ex. Structure and name Characterisation and procedure 69 [00173] .sup.1H NMR (DMSO-d6) δ 8.24 (d, J = 5.1 Hz, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.37 (s, 1H), 7.21 (dd, J = 1.7, 0.8 Hz, 1H), 7.09 (d, J = 7.7 Hz, 1H), 7.04 (d, J = 7.7 Hz, 1H), 7.02 (dd, J = 5.1, 1.7 Hz, 1H), 6.32 (d, J = 2.3 Hz, 1H), 4.50 (sept, J = 6.6 Hz, 1H), 2.88 (t, J = 7.5 Hz, 2H), 2.73 (t, J = 7.5 Hz, 2H), 2.06-1.88 (m, 3H), 1.40 (d, J = 6.7 Hz, 6H), 0.96-0.87 (m, 4H). LCMS m/z 466.0 (M + H).sup.+ (ES.sup.+). Intermediate R49 + known sulfonamide 70 [00174] .sup.1H NMR (DMSO-d6) δ 8.02 (d, J = 5.3 Hz, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.44 (s, 1H), 7.08 (d, J = 7.7 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.90 (dd, J = 5.3, 1.5 Hz, 1H), 6.77- 6.70 (m, 1H), 6.34 (s, 1H), 5.54-5.48 (m, 1H), 4.51 (sept, J = 6.8 Hz, 1H), 3.94 (dd, J = 10.2, 4.8 Hz, 1H), 3.90-3.83 (m, 1H), 3.82- 3.73 (m, 2H), 2.88 (t, J = 7.4 Hz, 2H), 2.69 (t, J = 7.5 Hz, 2H), 2.29-2.20 (m, 1H), 2.07- 1.99 (m, 1H), 1.94 (p, J = 7.5 Hz, 2H), 1.40 (d, J = 6.7 Hz, 6H). LCMS m/z 512.1 (M + H).sup.+ (ES.sup.+). Intermediate R46 + known sulfonamide 71 [00175] .sup.1H NMR (DMSO-d6) δ 8.07 (d, J = 5.3 Hz, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.40 (s, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.93 (dd, J = 5.3, 1.4 Hz, 1H), 6.81 (d, J = 1.3 Hz, 1H), 6.60 (d, J = 8.2 Hz, 1H), 6.30 (d, J = 2.3 Hz, 1H), 4.50 (t, J = 8.8 Hz, 2H), 4.22-4.12 (m, 1H), 3.78- 3.65 (m, 1H), 3.06 (t, J = 8.8 Hz, 2H), 1.06- 0.98 (m, 2H), 0.98-0.91 (m, 2H), 0.78- 0.71 (m, 2H), 0.71-0.64 (m, 2H). LCMS m/z 482.1 (M + H).sup.+ (ES.sup.+). Intermediate R53 + known sulfonamide 72 [00176] .sup.1H NMR (DMSO-d6) δ 8.07 (d, J = 5.2 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.37 (s, 1H), 7.08 (d, J = 7.7 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.95 (dd, J = 5.3, 1.4 Hz, 1H), 6.84 (d, J = 1.3 Hz, 1H), 6.29 (d, J = 2.3 Hz, 1H), 4.18 (tt, J = 6.3, 3.0 Hz, 1H), 3.72 (tt, J = 7.4, 3.9 Hz, 1H), 2.88 (t, J = 7.4 Hz, 2H), 2.73 (t, J = 7.5 Hz, 2H), 1.95 (p, J = 7.5 Hz, 2H), 1.09- 1.01 (m, 2H), 0.95 (td, J = 7.4, 4.9 Hz, 2H), 0.79-0.72 (m, 2H), 0.69-0.64 (m, 2H). LCMS m/z 480.1 (M + H).sup.+ (ES.sup.+). Intermediate R48 + known sulfonamide 73 [00177] .sup.1H NMR (DMSO-d6) δ 7.99 (d, J = 5.0 Hz, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.42 (s, 1H), 7.07 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.88 (dd, J = 5.3, 1.5 Hz, 1H), 6.74- 6.70 (m, 1H), 6.34 (d, J = 2.3 Hz, 1H), 5.20 (tt, J = 8.9, 4.1 Hz, 1H), 4.51 (sept, J = 6.7 Hz, 1H), 3.88 (dt, J = 11.7, 4.2 Hz, 2H), 3.56- 3.46 (m, 2H), 2.87 (t, J = 7.4 Hz, 2H), 2.69 (t, J = 7.5 Hz, 2H), 2.07-2.00 (m, 2H), 1.93 (p, J = 7.5 Hz, 2H), 1.71-1.59 (m, 2H), 1.40 (d, J = 6.7 Hz, 6H). LCMS m/z 526.1 (M + H).sup.+ (ES.sup.+). Intermediate R9 + known sulfonamide 74 [00178] .sup.1H NMR (DMSO-d6) δ 8.00 (d, J = 5.3 Hz, 1H), 7.74 (s, 1H), 7.44 (s, 1H), 7.08 (d, J = 8.2 Hz, 1H), 7.04 (d, J = 7.4 Hz, 1H), 6.88 (d, J = 5.3 Hz, 1H), 6.71 (d, J = 1.3 Hz, 1H), 6.35 (s, 1H), 5.05-4.99 (m, 1H), 4.51 (p, J = 6.4 Hz, 1H), 3.90 (dd, J = 11.2, 2.3 Hz, 1H), 3.69- 3.63 (m, 1H), 3.56-3.46 (m, 2H), 2.87 (t, J = 7.4 Hz, 2H), 2.69 (t, J = 7.5 Hz, 2H), 2.11- 2.03 (m, 1H), 1.93 (p, J = 7.5 Hz, 2H), 1.84- 1.71 (m, 2H), 1.61-1.52 (m, 1H), 1.40 (d, J = 6.6 Hz, 6H). LCMS m/z 526.1 (M + H).sup.+ (ES.sup.+). Intermediate R10 + known sulfonamide 75 [00179] .sup.1H NMR (DMSO-d6) δ 7.99 (d, J = 5.3 Hz, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.43 (s, 1H), 7.08 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.87 (dd, J = 5.3, 1.5 Hz, 1H), 6.70 (d, J = 1.3 Hz, 1H), 6.35 (s, 1H), 5.19-5.10 (m, 1H), 4.51 (sept, J = 6.6 Hz, 1H), 2.87 (t, J = 7.4 Hz, 2H), 2.69 (t, J = 7.5 Hz, 2H), 2.45- 2.38 (m, 2H), 2.12-2.03 (m, 2H), 1.93 (p, J = 7.5 Hz, 2H), 1.83-1.75 (m, 1H), 1.70-1.60 (m, 1H), 1.40 (d, J = 6.7 Hz, 6H). LCMS m/z 496.2 (M + H).sup.+ (ES.sup.+). Intermediate R47 + known sulfonamide 76 [00180] .sup.1H NMR (DMSO-d6) δ 8.01 (d, J = 5.3 Hz, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.44 (s, 1H), 7.08 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.88 (dd, J = 5.3, 1.5 Hz, 1H), 6.71 (d, J = 1.4 Hz, 1H), 6.34 (d, J = 2.3 Hz, 1H), 5.41- 5.35 (m, 1H), 4.51 (sept, J = 6.6 Hz, 1H), 2.91- 2.84 (m, 3H), 2.77-2.67 (m, 4H), 2.43 (q, J = 7.6 Hz, 1H), 2.34-2.26 (m, 4H), 1.93 (p, J = 7.5 Hz, 2H), 1.89-1.81 (m, 1H), 1.40 (d, J = 6.7 Hz, 6H). LCMS m/z 525.2 (M + H).sup.+ (ES.sup.+). Intermediate R37 + known sulfonamide 77 [00181] .sup.1H NMR (DMSO-d6) δ 8.03-7.97 (m, 1H), 7.69-7.64 (m, 1H), 7.51-7.39 (m, 3H), 7.20 (t, J = 7.4 Hz, 1H), 7.16 (d, J = 7.5 Hz, 2H), 7.11-7.03 (m, 3H), 6.98 (s, 1H), 6.40-6.24 (m, 1H), 4.47 (sept, J = 6.6 Hz, 1H), 2.89 (t, J = 7.4 Hz, 2H), 2.73 (t, J = 7.4 Hz, 2H), 1.95 (p, J = 7.5 Hz, 2H), 1.39 (d, J = 6.7 Hz, 6H). m/z 518.1 (M + H).sup.+ (ES.sup.+); 516.4 (M − H).sup.− (ES.sup.−). Intermediate R11 + known sulfonamide

Example 78: N′-((5-(2-((1-Methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)benzenesulfonimidamide

[0489] ##STR00182##

[0490] NaOtBu (2M in THF, 0.051 mL, 0.102 mmol) was added to a stirred suspension of N′-(tert-butyldimethylsilyl)benzenesulfonimidamide (Intermediate L6) (25 mg, 0.092 mmol) in THF:DMF (4:1, 1 mL). The reaction mixture was stirred for 30 minutes at room temperature. Then phenyl (5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamate (Intermediate R.sup.38) (41 mg, 0.092 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc (30 mL), washed with water (30 mL), dried using a phase separator, and concentrated in vacuo to afford the TBS protected product. This was cooled to 0° C., taken up in HCl (4M in dioxane) (2 mL, 8.00 mmol) and stirred at this temperature for 1 hour. Then the reaction mixture was concentrated in vacuo and the resulting residue was purified by basic prep HPLC (20-50% MeCN in water) to afford the title compound (15 mg, 32%) as a white powder.

[0491] .sup.1H NMR (DMSO-d6) δ 8.31 (br s, 1H), 8.08 (d, J=5.3 Hz, 1H), 7.87-7.67 (m, 2H), 7.65-7.48 (m, 3H), 7.44-7.27 (m, 2H), 7.15 (d, J=7.7 Hz, 1H), 7.07 (d, J=7.7 Hz, 1H), 6.89-6.80 (m, 1H), 6.75-6.63 (m, 1H), 5.08-4.98 (m, 1H). 2.90 (t, J=7.5 Hz, 2H), 2.83-2.62 (m, 4H), 2.38-2.13 (m, 5H), 2.09-1.90 (m, 4H), 1.79-1.65 (m, 2H).

[0492] LCMS m/z 506.4 (M+H).sup.+ (ES.sup.+); 504.2 (M−H).sup.− (ES.sup.−).

Example 79: N-((6-Methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)benzenesulfonimidamide

Step A

N-((6-Methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)benzenesulfinamide

[0493] ##STR00183##

[0494] To a solution of benzenesulfinamide (Intermediate L7) (50 mg, 354.13 μmol, 1 eq) in THF (1 mL) was added with t-BuONa (102 mg, 1.06 mmol, 3 eq) at 25° C. The reaction mixture was stirred at 25° C. for 30 minutes. Then phenyl (6-methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamate (Intermediate R.sup.67) (202 mg, 354.13 μmol, 1 eq, TFA salt) was added. The resulting mixture was stirred at 25° C. for 5 hours. Then the reaction mixture was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O-MeCN) to give the title compound (120 mg, 59% yield, 88% purity on LCMS) as a white solid.

[0495] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.57-9.27 (m, 1H), 8.31-8.17 (m, 1H), 7.71-7.42 (m, 5H), 7.24-7.07 (m, 1H), 6.82-6.65 (m, 1H), 6.51 (s, 1H), 5.11-4.93 (m, 1H), 3.48-3.41 (m, 2H), 2.99-2.68 (m, 5H), 2.24-1.96 (m, 11H) and 1.89-1.61 (m, 2H). 1×NH was missing.

[0496] LCMS: m/z 505.3 (M+H).sup.+ (ES.sup.+).

Step B

N-((6-Methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)benzenesulfonimidamide

[0497] ##STR00184##

[0498] To a solution of N-((6-methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)benzenesulfinamide (0.1 g, 198.16 μmol, 1 eq) in THF (1 mL) was added 1-chloro-H-benzo[d][1,2,3]triazole (27 mg, 178.34 μmol, 0.9 eq). The reaction mixture was stirred at 25° C. for 30 minutes. Then the reaction mixture was added into a solution of NH.sub.3/THF (5 mL) at −70° C.; NH.sub.3 was bubbled into THF for 5 minutes to afford the NH.sub.3/THF solution. After addition, the mixture was stirred at −70° C. for 30 minutes. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep-TLC (SiO.sub.2, DCM:methanol, 10:1) and then further purified by prep HPLC (column: Phenomenex luna C18, 150 mm×25 mm×10 μm; mobile phase [A: water (0.1% TFA); B: MeCN]; B %: 22%-42%, 10 minutes) to give the title compound (21.45 mg, 17% yield, 100% purity on LCMS, TFA salt) as a white solid.

[0499] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.22-8.10 (m, 1H), 8.02-7.80 (m, 2H), 7.68-7.46 (m, 3H), 7.10 (d, 1H), 6.83-6.62 (m, 2H), 5.45-5.21 (m, 1H), 3.93-3.40 (m, 2H), 3.38-301 (m, 2H), 3.00-2.71 (m, 7H), 2.49-2.19 (m, 4H) and 2.17-1.96 (m, 5H). 3×NHs were missing.

[0500] LCMS: m/z 520.1 (M+H).sup.+ (ES.sup.+).

Example 80: N-((6-Methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)methanesulfonimidamide

Step A: N-((6-Methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)methanesulfinamide

[0501] ##STR00185##

[0502] Sodium tert-butoxide (134 mg, 1.40 mmol, 1.6 eq) was added into a mixture of methanesulfinamide (Intermediate L8) (103 mg, 1.31 mmol, 1.5 eq) in THF (2 mL) at 20° C. The reaction mixture was stirred at 20° C. for 30 minutes. Then phenyl (6-methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamate (Intermediate R.sup.67) (400 mg, 874.20 μmol, 1 eq) was added at 20° C. and the resulting mixture was stirred at 20° C. for 30 minutes. The reaction mixture was poured into ice-water (30 mL). The aqueous phase was extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O-MeCN) to afford the title compound (150 mg, 26% yield, 68% purity on LCMS) as a white solid.

[0503] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.17 (d, 1H), 7.14 (d, 1H), 6.71-6.65 (m, 1H), 6.54 (d, 1H), 5.08-5.04 (m, 1H), 2.97 (t, 2H), 2.87 (t, 2H), 2.75-2.73 (m, 2H), 2.64 (s, 3H), 2.33-2.27 (m, 5H), 2.15-2.07 (m, 7H) and 1.86-1.73 (m, 2H). 2×NHs were missing.

[0504] LCMS: m/z 443.4 (M+H).sup.+ (ES.sup.+).

Step B: N-((6-Methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)methanesulfonimidamide

[0505] ##STR00186##

[0506] To a solution of N-((6-methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)methanesulfinamide (250 mg, 564.88 μmol, 1 eq) in THF (5 mL) was added 1-chloro-1H-benzo[d][1,2,3]triazole (78 mg, 508.39 μmol, 0.9 eq) at 20° C. The reaction mixture was stirred for 30 minutes at 20° C. Then the reaction mixture was added into a solution of NH.sub.3/THF at −78° C.; NH.sub.3 gas (15 psi) was bubbled into THF (5 mL) for 5 minutes to afford the NH.sub.3/THF solution. The resulting mixture was stirred at −78° C. for 20 minutes, and then warmed to 20° C. and stirred for 2 hours. Then the reaction mixture was concentrated in vacuo. The residue was purified by prep HPLC (column: Xtimate C18, 150 mm×40 mm×10 μm; mobile phase [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 19%-49%, 10 minutes) to afford the title compound (2.19 mg, 1% yield, 99.8% purity on LCMS) as a yellow solid.

[0507] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.12 (d, 1H), 7.09 (s, 1H), 6.82 (d, 1H), 6.69 (s, 1H), 5.14-5.12 (m, 1H), 3.21 (s, 3H), 3.03-3.01 (m, 2H), 2.95 (t, 2H), 2.88 (t, 2H), 2.83-2.57 (m, 2H), 2.55 (s, 3H) and 2.14-1.92 (m, 9H). 3×NHs were missing.

[0508] LCMS: m/z 458.3 (M+H).sup.+ (ES.sup.+).

Example 81: 1-(N-Cyano-S-methyl-sulfonimidoyl)-3-(6-methyl-5-(2-((1-methyl-4-piperidyl)oxy)-4-pyridyl)indan-4-yl)urea

[0509] ##STR00187##

[0510] To a mixture of N-((6-methyl-5-(2-((1-methylpiperidin-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)methanesulfonimidamide (Example 80) (30 mg, 65.56 μmol, 1 eq) and triethylamine (27 mg, 262.24 μmol, 4 eq) in DMF (1 mL) was added cyanic bromide (14 mg, 131.12 μmol, 2 eq) at 25° C. The reaction mixture was stirred at 25° C. for 12 hours, and then quenched with water (0.5 mL) and concentrated in vacuo. The residue was purified by prep HPLC (column: Phenomenex Gemini-NX C18, 75 mm×30 mm×3 m; mobile phase [A: water (0.1% TFA), B: MeCN]; B %: 20%-30%, 7 minutes) to afford the title compound (21.8 mg, 54% yield, 97.6% purity on HPLC, TFA salt) as yellow oil.

[0511] .sup.1H NMR (400 MHz, DMSO-d6+D.sub.2O) δ 8.16 (t, 1H), 7.09 (s, 1H), 6.79 (t, 1H), 6.63 (d, 1H), 5.27-5.13 (m, 1H), 3.48-3.45 (m, 1H), 3.35-3.32 (m, 1H), 3.27-3.12 (m, 5H), 2.88 (t, 2H), 2.81-2.75 (m, 5H), 2.34-2.30 (m, 1H), 2.18-2.13 (m, 1H), 3.05-1.96 (m, 6H) and 1.83-1.75 (m, 1H). 2 X NHs were missing.

[0512] LCMS: m/z 483.2 (M+H).sup.+ (ES.sup.+).

EXAMPLES—BIOLOGICAL STUDIES

NLRP and Pyroptosis

[0513] It is well established that the activation of NLRP3 leads to cell pyroptosis and this feature plays an important part in the manifestation of clinical disease (Yan-gang Liu et al., Cell Death & Disease, 2017, 8(2), e2579; Alexander Wree et al., Hepatology, 2014, 59(3), 898-910; Alex Baldwin et al., Journal of Medicinal Chemistry, 2016, 59(5), 1691-1710; Ema Ozaki et al., Journal of Inflammation Research, 2015, 8, 15-27; Zhen Xie & Gang Zhao, Neuroimmunology Neuroinflammation, 2014, 1(2), 60-65; Mattia Cocco et al., Journal of Medicinal Chemistry, 2014, 57(24), 10366-10382; T. Satoh et al., Cell Death & Disease, 2013, 4, e644). Therefore, it is anticipated that inhibitors of NLRP3 will block pyroptosis, as well as the release of pro-inflammatory cytokines (e.g. IL-1β) from the cell.

THP-1 Cells: Culture and Preparation

[0514] THP-1 cells (ATCC #TIB-202) were grown in RPMI containing L-glutamine (Gibco #11835) supplemented with 1 mM sodium pyruvate (Sigma #S8636) and penicillin (100 units/ml)/streptomycin (0.1 mg/ml) (Sigma #P4333) in 10% Fetal Bovine Serum (FBS) (Sigma #F0804). The cells were routinely passaged and grown to confluency (˜10.sup.6 cells/ml). On the day of the experiment, THP-1 cells were harvested and resuspended into RPMI medium (without FBS). The cells were then counted and viability (>90%) checked by Trypan blue (Sigma #T8154). Appropriate dilutions were made to give a concentration of 625,000 cells/ml. To this diluted cell solution was added LPS (Sigma #L4524) to give a 1 μg/ml Final Assay Concentration (FAC). 40 μl of the final preparation was aliquoted into each well of a 96-well plate. The plate thus prepared was used for compound screening.

THP-1 Cells Pyroptosis Assay

[0515] The following method step-by-step assay was followed for compound screening. [0516] 1. Seed THP-1 cells (25,000 cells/well) containing 1.0 μg/ml LPS in 40 μl of RPMI medium (without FBS) in 96-well, black walled, clear bottom cell culture plates coated with poly-D-lysine (VWR #734-0317) [0517] 2. Add 5p compound (8 points half-log dilution, with 100M top dose) or vehicle (DMSO 0.1% FAC) to the appropriate wells [0518] 3. Incubate for 3 hrs at 37° C., 5% CO.sub.2 [0519] 4. Add 5 μl nigericin (Sigma #N7143) (FAC 5 μM) to all wells [0520] 5. Incubate for 1 hr at 37° C., 5% CO.sub.2 [0521] 6. At the end of the incubation period, spin plates at 300×g for 3 mins and remove supernatant [0522] 7. Then add 50 μl of resazurin (Sigma #R7017) (FAC 100 μM resazurin in RPMI medium without FBS) and incubate plates for a further 1-2 hrs at 37° C. and 5% CO.sub.2 [0523] 8. Plates were read in an Envision reader at Ex 560 nm and Em 590 nm [0524] 9. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

96-Well Plate Map

[0525]

TABLE-US-00015 1 2 3 4 5 6 7 8 9 10 11 12 A High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low B High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low C High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low D High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low E High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low F High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low G High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low H High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low High MCC950 (10 uM) Compound 8-point half-log dilution Low Drug free control

[0526] The results of the pyroptosis assay are summarised in Table 1 below as THP IC.sub.50.

Human Whole Blood IL-1μ Release Assay

[0527] For systemic delivery, the ability to inhibit NLRP3 when the compounds are present within the bloodstream is of great importance. For this reason, the NLRP3 inhibitory activity of a number of compounds in human whole blood was investigated in accordance with the following protocol.

[0528] Human whole blood in Li-heparin tubes was obtained from healthy donors from a volunteer donor panel. [0529] 1. Plate out 8 μl of whole blood containing 1 μg/ml of LPS in 96-well, clear bottom cell culture plate (Corning #3585) [0530] 2. Add 1 μl compound (8 points half-log dilution with 10 M top dose) or vehicle (DMSO 0.1% FAC) to the appropriate wells [0531] 3. Incubate for 3 hrs at 37° C., 5% CO.sub.2 [0532] 4. Add 1 μl nigericin (Sigma #N7143) (10M FAC) to all wells [0533] 5. Incubate for 1 hr at 37° C., 5% CO.sub.2 [0534] 6. At the end of the incubation period, spin plates at 300×g for 5 mins to pellet cells and remove 20 μl of supernatant and add to 96-well v-bottom plates for IL-1β analysis (note: these plates containing the supernatants can be stored at −80° C. to be analysed at a later date) [0535] 7. IL-1β was measured according to the manufacturer protocol (Perkin Elmer-AlphaLisa IL-1 Kit AL220F-5000) [0536] 8. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

[0537] The results of the human whole blood assay are summarised in Table 1 below as HWB IC.sub.50.

[0538] For comparison, three compounds outside the scope of the claims are included in Table 1:

TABLE-US-00016 TABLE 1 [00188] [00189] [00190] Exam- ple No THP IC.sub.50 HWB IC.sub.50  1 ++++++ +++  4 ++++++ +++++  8 +++++ +++ 15 +++++ +++++ 19 ++++++ +++ 22 ++++++ ++ 27 +++ ++++ 29 ++++++ ++++++ 33 +++++ +++ 35 ++++++ ++++++ 39 ++++++ +++ 41 ++++++ +++ 42 +++ +++ 43 ++++ ++++++ 44 ++++++ +++++ 45 ++++++ ++++++ 46 ++++++ ++++++ 47 ++++++ ++++++ 48 ++++++ ++++++ 49 ++++++ ++++++ 50 ++++++ ++++++ 51 ++++++ ++++++ 52 +++++ +++++ 53 ++++++ +++++ 54 ++++++ ++++ 55 ++++++ ++++ 56 ++++++ ++++ 57 ++++++ +++ 58 ++++++ ++ 59 ++++++ +++ 60 ++++++ ++++ 62 ++++++ +++++ 64 ++++++ +++++ 65 ++++++ +++++ 66 ++++++ +++++ 67 ++++++ ++++ 68 ++++++ +++++ 69 ++++++ ++++ 70 ++++++ ++++ 71 ++++++ ++++ 72 ++++++ +++ 73 ++++++ ++++ 74 ++++++ +++ 75 ++++++ +++ 76 ++++ ND 77 ++++++ + 78 ++++++ ++ 79 ++++++ +++ 80 ++++++ ++++ comp ex 1 +++ inactive comp ex 2 ++ ND comp ex 3 ++ ND NLRP.sub.3 inhibitory activity (≤0.25 μM = ‘++++++’, ≤0.5 μM = ‘+++++’, ≤1 μM = ‘++++’, ≤2 μM = ‘+++’, ≤5 μM = ‘++’, ≤10 μM = ‘+’, >10 μM = ‘inactive’, not determined = ‘ND’).

[0539] As is evident from the results presented in Table 1, surprisingly in spite of the structural differences versus the prior art compounds, the compounds of the invention show high levels of NLRP3 inhibitory activity in the pyroptosis assay and in particular in the human whole blood assay.

[0540] It will be understood that the present invention has been described above by way of example only. The examples are not intended to limit the scope of the invention. Various modifications and embodiments can be made without departing from the scope and spirit of the invention, which is defined by the following claims only.